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BASAL CELL CARCINOMA, SPORADIC (BCC)

IntroductionBasal cell carcinoma occurs most often on areas of the body frequently exposed to the sun –  the face, ear

neck, scalp, shoulders, and back. Tumors sometimes develop on areas not often exposed to the sun, but this is rarOther contributing factors are exposure to or contact with arsenic

radiation, or complications from burns, scars, or tattoos.Basal cell carcinoma sometimes resembles psoriasis or eczemtherefore, a physician should examine your skin regularly and sugge

regular time intervals for examination depending upon your ri

factors. Watch for changes in size, color, texture, and appearance,

well as skin pain, bleeding, itching, or inflammation. Commocharacteristics of basal cell carcinoma include a bleeding or no

healing sore, a reddish patch, a shiny bump, a pink growth, or

scarred area.

Genetic Factors

Mutations in the gene coding for the transmembrane receptor protein PTCH, or PTCH1, are associated wi basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH , the human homolog

the Drosophila segment polarity gene patched  ( ptc), is an integral component of the hedgehog signaling pathwa

which serves many developmental (appendage development, embryonic segmentation, neural tube differentiatio

and regulatory (maintenance of stem cells) roles.In the resting state, the transmembrane receptor protein PTCH acts catalytically to suppress the seven

transmembrane protein Smoothened (Smo), preventing further downstream signal transduction. Stoichiometr

 binding of the hedgehog ligand to PTCH releases inhibition of Smo, with resultant activatioof  transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E , myc), and regulators

angiogenesis. Thus, the balance of PTCH (inhibition) and Smo (activation) manages the essential regulato

downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH or gain-of-functio

mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformationDemonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested th

 potential presence of an associated tumor suppressor gene. Further investigation identified a mutation in PTCH  th

localized to the area of allelic loss. Up to 30% of sporadic BCCs demonstrate  PTCH  mutations. In addition BCC, medulloblastoma and rhabdomyosarcoma, along with other human tumors, have been associatewith PTCH  mutations. All three malignancies are associated with BCNS, and most people with clinical features

BCNS demonstrate PTCH  mutations, predominantly truncation in type.

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, has beendemonstrated in both BCC and medulloblastoma. PTCH2 displays 57% homology to PTCH1, differing in the

conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal

extension. While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the

hedgehog signaling pathway.The risk of skin cancer is much higher for whites than for African Americans or Hispanics. This is due to

the protective effect of the skin pigment melanin in people with darker skin. Whites with fair (light-colored) skin

that freckles or burns easily are at especially high risk. This is one of the reasons for the high skin cancer rate inAustralia, where much of the population descends from fair-skinned immigrants from the British Isles. Albinism

is a congenital (present at birth) lack of protective skin pigment. People with this condition may have pink-white

skin and white hair. They have a high risk of getting skin cancer unless they are careful to protect their skin.The risk of basal and squamous cell skin cancers rises as people get older. This is probably because of the

 buildup of sun exposure over time. These cancers are now being seen in younger people as well, probably because

they are spending more time in the sun with their skin exposed.

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Men are about twice as likely as women to have basal cell cancers and about 3 times as likely to havesquamous cell cancers of the skin. This is thought to be due mainly to higher levels of sun exposure

Epidemiology 

Light-colored skin and sun exposure are both important factors in the development of basal cell carcinoma

About 20% of these skin cancers, however, occur in areas that are not sun-exposed, such as the chest, back, arm

legs, and scalp. The face, however, remains the most common location for basal cell lesions. Weakening of thimmune system, whether by disease or  medication, can also promote the risk of developing basal cell carcinoma.

According to the U.S. National Institutes of Health, ultraviolet (UV) radiation from the sun is the macause of skin cancer. Artificial sources of UV radiation, such as sunlamps and tanning booths, can also  cause sk

cancer. The risk of developing skin cancer is also affected by where a person lives. People who live in areas th

receive high levels of UV radiation from the sun are more likely to develop skin cancer. In the U.S., for exampl

skin cancer is more common in Texas than it is in Minnesota, where the sun is not as strong. Worldwide, thhighest rates of skin cancer are found in South Africa, Israel, New Zealand, and Australia, which are areas th

receive high amounts of UV radiation. Most skin cancers appear after age 50, but the sun's damaging effects beg

at an early age. Therefore, protection should start in childhood in order to prevent skin cancer later in life.

Diagnostic Procedures

Skin biopsyIf the doctor thinks that a suspicious area might be skin cancer, he or she will take a sample of skin fro

the area and have it looked at under a microscope. This procedure is called a skin biopsy. If the biopsy removthe entire tumor, it is often enough to cure basal and squamous cell skin cancers without further treatment.

There are different ways to do a skin biopsy. The doctor will choose one based on the suspected type

skin cancer, where it is on your body, the size of the affected area, and other factors. Any biopsy is likely to leavat least a small scar. Different methods may result in different scars, so ask your doctor about possible scarrin

 before the biopsy is done. No matter which type of biopsy is done, it should remove as much of the suspected ar

as possible so that an accurate diagnosis can be made. Skin biopsies are done using a local anesthetic (numbin

medicine), which is injected into the area with a very small needle. You will probably feel a small prick and a littstinging as the medicine is injected, but you should not feel any pain during the biopsy.

Shave biopsyFor a shave biopsy, the doctor first numbs the area with a local anesthetic. The doctor then shaves off the

top layers of the skin with a small surgical blade. Usually the epidermis and the outer part of the dermis are

removed, although deeper layers can be taken as well if needed. Bleeding from the biopsy site is then stopped byapplying an ointment or a small electrical current to cauterize the wound.

Punch biopsyA punch biopsy removes a deeper sample of skin. The doctor uses a tool that looks like a tiny round cook

cutter. Once the skin is numbed with a local anesthetic, the doctor rotates the punch biopsy tool on the surface the skin until it cuts through all the layers of the skin, including the dermis, epidermis, and the upper parts of t

subcutis. The edges of the biopsy site are then stitched together.

Incisional and excisional biopsies

To examine a tumor that may have grown into deeper layers of the skin, the doctor may use an incisionor excisional biopsy. An incisional biopsy removes only a portion of the tumor. An excisional biopsy removes th

entire tumor. After numbing the area with a local anesthetic, a surgical knife is used to cut through the fu

thickness of skin. A wedge or sliver of skin is removed for examination, and the edges of the wound are stitchtogether.

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Examining the biopsy samplesAll skin biopsy samples are sent to a lab, where they are looked at under a microscope by a pathologist

doctor trained in looking at tissue samples to diagnose disease). Often, the samples are sent to

dermatopathologist, a doctor who has special training in making a diagnosis from skin samples.

Lymph node biopsyRarely, when basal or squamous cell skin cancer spreads, it usually goes first to nearby lymph node

which are small, bean-shaped collections of immune cells. If your doctor feels lymph nodes near the tumor that a

too large and/or too firm, a lymph node biopsy may be done to determine whether cancer has spread to them. Fi

needle aspiration biopsy A fine needle aspiration (FNA) biopsy uses a syringe with a thin, hollow needle remove very small tissue fragments. The needle is smaller than the needle used for a blood test. A local anesthet

is sometimes used to numb the area first. This test rarely causes much discomfort and does not leave a scar.

An FNA biopsy is not used to diagnose a suspicious skin tumor, but it may be used to biopsy large lympnodes near a skin cancer to find out if the cancer has spread to them. FNA biopsies are not as invasive as som

other types of biopsies, but they may not always provide enough of a sample to find cancer cells.

Surgical (excisional) lymph node biopsyIf an FNA does not find cancer in a lymph node but the doctor still suspects the cancer has spread there, t

lymph node may be removed by surgery and examined. This can often be done in a doctor's office or outpatie

surgical center using local anesthesia and will leave a small scar.

References:Skin Cancer: Basal Cell Carcinoma (2013, 20 September). Retrieved from

http://www.cap.org/apps/docs/reference/myBiopsy/SkinBasalCellCarcinoma.pdf

Genetics of Skin Cancer (PDQ®) (2013). Retrieved from:

http://www.cancer.gov/cancertopics/pdq/genetics/skin/HealthProfessional/page2#Section_12

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CRANIOSYNOSTOSIS, TYPE 1

IntroductionCraniosynostosis consists of premature fusion of 1 or more cranial sutures, often resulting in an abnorm

head shape. It may result from a primary defect of ossification (primary craniosynostosis) or, more commonl

from a failure of brain growth (secondary craniosynostosis). Simple craniosynostosis is a term used when only suture fuses prematurely. Complex or compound craniosynostosis is used to describe premature fusion of multip

sutures. When children with craniosynostosis, usually complex, also display other body deformities, this is terme

syndromic craniosynostosis.Symptoms depend on the type of craniosynostosis. They may include: no "soft spot" (fontanelle) on th

newborn's skull, a raised hard ridge along the affected sutures, unusual head shape, and slow or no increase in th

head size over time as the baby grows

Sagittal synostosis (scaphocephaly) is the most common type. It affects the main suture on the very top othe head. The early closing forces the head to grow long and narrow, instead of wide. Babies with this type tend

have a broad forehead. It is more common in boys than girls.

Frontal plagiocephaly is the next most common type. It affects the suture that runs from ear to ear on th

top of the head. It is more common in girls.Metopic synostosis is a rare form that affects the suture close to the forehead. The child's head shape ma

 be described as trigonocephaly. It may range from mild to severe.

Multiple theories have been proposed for the etiology of primary craniosynostosis, but the most wideaccepted is a primary defect in the mesenchymal layer ossification in the cranial bones.

Secondary craniosynostosis typically results from systemic disorders such as the following:  Endocrine - Hyperthyroidism, hypophosphatemia, vitamin D deficiency, renal osteodystroph

hypercalcemia, and rickets

  Hematologic disorders that cause bone marrow hyperplasia (eg, sickle cell disease, thalassemia  Inadequate brain growth, including microcephaly and its causes and shunted hydrocephalus

The syndromic causes appear to result from genetic mutations responsible for fibroblast growth factreceptors 2 and 3. A gene locus for single suture craniosynostosis has not been identified.[6]

Differentiating plagiocephaly that results from positional molding (which does not require surgery and

seen frequently) from lambdoid suture fusion is extremely important. The presence of multiple suture fusionstrongly suggests a craniofacial syndrome, which frequently requires the diagnostic expertise of a pediatr

geneticist.

Craniofacial morphogenesis is highly dependent on the patterning information of emigrant cranial neur

crest (CNC) cells. CNC cells give rise to a wide variety of tissues and structures, including skull bones. Durinskull development, cranial sutures serve as growth centers for skeletogenesis that is mediated throug

intramembranous ossification. This process differs from endochondral ossification in the appendicular and axi

skeletons, where prior formation of cartilage templates is required. Axin2 is highly expressed in CNC cells andeveloping sutures neural crest (nasal and frontal bones) but not mesoderm (parietal bones). Depende

osteogenesis is particularly sensitive to the loss of Axin2.

Genetic FactorsMost cases of syndromic craniosynostosis are caused by one of four genetic mutations. A genetic mutatio

occurs when instructions carried in certain genes (a unit of genetic material) become scrambled. This means som

of the body's processes do not work in the normal way.Examples of mutated genes in craniosynostosis are:

  FGFR1, FGFR2 and FGFR3 (three related genes)  TWIST gene

The FGFR group of genes seem to make a protein called fibroblast growth factor receptor work le

effectively. As this protein is involved in regulating cell growth, particularly the growth of bones, it is thought th

FGFR mutation disrupts the development of the skull.

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The mutated TWIST gene seems to totally block the effects of fibroblast growth factor receptors. There aroften a wide range of birth defects associated with this gene.

EpidemiologyIncidence of craniosynostosis is 0.04-0.1%. Of affected individuals, 2-8% have primary craniosynostosi

The remaining cases are secondary craniosynostosis, which frequently is accompanied by microcephaly. Th

frequencies of the various types of craniosynostosis are as follows: sagittal 50-58%, coronal 20-29%, metopic

10%, and lambdoid 2-4%.Raised intracranial pressure is rare with fusion of a single suture. It can occur in primary craniosynostos

when multiple sutures fuse. Primary craniosynostosis: Although the major morbidity is due to the abnormal shap

of the skull, intracranial pressure can be elevated. This occurs with a high frequency in multiple suture synostosand rarely with single suture synostosis. Secondary craniosynostosis: Typically no morbidity is noted, except th

related to the underlying disorder. The lack of brain growth often is associated with neurodevelopmental dela

Craniosynostosis of 1-2 sutures: Cosmetic defect is the primary morbidity.

Craniosynostosis is equally distributed in both boys and girls. Neonatal period: Craniosynostosis is evideat birth when associated with other craniofacial abnormalities. Infancy (0-18 mo): Secondary or prima

craniosynostosis becomes evident as the child grows.

Diagnostic Procedures

Craniosynostosis can usually be diagnosed by a paediatrician(specialist in treating children) after a visual examination of your baby's

head. Any severe distortions of the skull or face will be apparent, and

the existence of ridges over fused sutures or misalignment of the earswill also provide evidence of craniosynostosis. An X-ray of the skull

may be taken to confirm a diagnosis of craniosynostosis.

A computerised tomography (CT) scan is the most detailed

method of assessing the condition of your child's skull. A CT scaninvolves taking a series of X-rays and using a computer to reassemble

them into a more detailed image. CT scans are usually only required to plan some types of surgery or if thdiagnosis of craniosynostosis is in doubt.

References:

Craniosynostosis - Causes - NHS Choices. Retrieved September 23, 2013, fro

http://www.nhs.uk/Conditions/Craniosynostosis/Pages/Causes.aspx 

Jabs EW. Toward understanding the pathogenesis of craniosynostosis through clinical and molecul

correlates. Clin Genet . Feb 1998;53(2):79-86. [Medline]. 

Kinsman SL, Johnston MV. Craniosynostosis.In: Kliegman RM,Behrman RE, Jenson HB, Stanton BF, ed(2011). Nelson Textbook of Pediatrics.19th ed. Philadelphia, Pa: Saunders Elsevier. 

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CURRARINO SYNDROME

IntroductionThe Currarino symdrome involves the association of partial sacral agenesis with intact first sacral verteb

('sickle-shaped sacrum'), a presacral mass, and anorectal malformation . The specific sacral anomaly is distinct

this syndrome. Associated malformations include rectovaginal fistula, tethering of the cord, duplex urete

hydronephrosis, vesicoureteral reflux, bicornuate uterus, and neurogenic bladder. Malignant degeneration of th presacral teratoma has also been reported.

The term Currarino syndrome is preferred as it is now known that there are other components to this genet

disorder. Bowel obstruction in infancy or chronic constipation in childhood are the commonest presentin

symptoms. Gynaecological and renal malformation are commonly described. Hirschsprungs disease and meningit(often E Coli ascending meningitis) have been recorded. Perianal sepsis, which is found in at least 10% of patient

can indicate the presence of an underlying presacral mass. Tumour development within the teratoma has bee

documented. A report describing Currarino syndrome

with ventriculomegaly due to a Arnold-Chiari type IImalformation must be interpreted with caution. The

affected child was dysmorphic with hypertelorism, a

short enlarged neck and camptodactyly. The mother and brother also had Currarino syndrome without these

added features. It is quite possible that this child had two

co-existing disorders, one the Currarino inherited from a

mother with typical features and secondly a de novoArnold-Chiari type II malformation.

As with many dominant disorders the phenotype

is very variable. It is estimated that approximately 50%of those who inherit the gene will present with the

severe phenotype (requiring surgery), 25% will have

symptoms albeit milder and 25% will be asymptomatic

heterozygotes.

Genetic FactorsThe disorder is an autosomal dominant genetic trait caused by a mutation in the HLXB9 homeobox gene.

2000 the first large series of Currarino cases was genetically screened for HLXB9 mutations, and it was showe

that the gene is specifically causative for the syndrome, but not for other forms of sacral agenesis

The HLXB9 gene functions as a transcription factor regulating gene expression in both developing an

adult tissues. Little is known about target genes or protein partners.

Epidemiology

Expressivity is variable, which makes it difficult to evaluate the true prevalence of the syndrome: 39%  patients present with a severe phenotype, 29% are clinically apparent, 28% have X-ray changes only, and 4% aasymptomatic. Females are more frequently affected, they often have associated gynecological and urinary tra

 problems. Age at presentation varies greatly, ranging from birth to 64 years. All first-degree relatives should b

offered a pelvic X-ray. Those with an abnormal x-ray should be referred to a surgeon for further investigation. Infew cases, deletions of 7q were reported. Prenatal diagnosis is rarely made, and relies on the detection of

sacrococcygeal mass. Mutational or linkage analysis on fetal cells is possible providing the mutation is known o

the family structure is suitable.

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Diagnostic ProceduresCytogenetic analysis will be normal in most cases. However, some cases are associated with a 7q36 deletion or

translocation involving this region. It is worth considering FISH analysis of 7q36 in cases where Currarin

syndrome is associated with developmental delay

In radiologic test, The first sacral vertebra is not affected, and the hemi-sacrum below usually takes the form of

sickle or crescent with the so-called scimitar sign at X-rays.

Reference:

GeneReviews. (2005). Seattle, WA: University of Washington. Available :  http://www.ncbi.nlm.nih.gov/books/NBK51784/

Lynch SA . (June 2007) Currarino syndrome. Atlas Genet Cytogenet Oncol Haematol. . Retrive

from: http://AtlasGeneticsOncology.org/Kprones/CurrarinoID10082.html

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GREIG CEPHALOPOLYSYNDACTYLY SYNDROME (GCS)

Introduction

Greig cephalopolysyndactyly syndrome is a disorder that affects

development of the limbs, head, and face. The features of this syndrome are

highly variable, ranging from very mild to severe. People with this condition

typically have one or more extra fingers or toes (polydactyly) or anabnormally wide thumb or big toe (hallux). The skin between the fingers and

toes may be fused (cutaneous syndactyly). This disorder is also characterized

 by widely spaced eyes (ocular hypertelorism), an abnormally large head size(macrocephaly), and a high, prominent forehead. Rarely, affected individuals

may have more serious medical problems including seizures, developmental

delay, and intellectual disability.

Genetic Factors

Mutations in the GLI3 gene cause Greig cephalopolysyndactyly syndrome. The GLI3 gene providinstructions for making a protein that controls gene expression, which is a process that regulates whether genes arturned on or off in particular cells. By interacting with certain genes at specific times during development, th

GLI3 protein plays a role in the normal shaping (patterning) of many organs and tissues before birth.

Different genetic changes involving the GLI3 gene can cause Greig cephalopolysyndactyly syndrome.

some cases, the condition results from a chromosomal abnormality — such as a large deletion or rearrangement genetic material — in the region of chromosome 7 that contains the GLI3 gene. In other cases, a mutation

the GLI3 gene itself is responsible for the disorder. Each of these genetic changes prevents one copy of the gene

each cell from producing any functional protein. It remains unclear how a reduced amount of this protein disrup

early development and causes the characteristic features of Greig cephalopolysyndactyly syndrome.

Epidemiology

This condition is very rare; its prevalence is unknown.

Diagnostic Procedures

1.  Cytogenetic analysis. Giemsa-banding karyotype performed at the 500-600 band level with attentio

directed to 7p13 detects atranslocation or interstitial deletion in fewer than 5%-10% of  affected individua

 Note: Giemsa-banded karyotypes do not detect all deletions, even those on the order of 1 Mb [unpublisheobservations].

2.  Molecular Genetic Testing. GLI3 is the only gene in which mutation isknown to be associated with Gre

cephalopolysyndactyly syndrome. 

3.  Clinical testing

a.  Sequence analysis detects mutations in approximately 70% of typically affected individuals 

b.  Duplication/deletion testing.

i.  FISH analysis using hybridization of the labeled BAC clone to metaphase spreads detec

deletions in the estimated 5%-10% of individuals with large deletions

ii.  Array comparative genomic hybridization (array CGH) of GLI3. No data have be published on use of this method to detect GLI3 deletions but it is reasonable to expect th

array CGH would detect a deletion that encompasses more than one target on the array. 

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iii.  MLPA (multiplex ligation-dependent probe amplification). The general utility of MLPA well established; however, no data demonstrating the specificity or  sensitivity of th

technique for GLI3 deletions or duplications have been published. 

4.  Research testing.  Molecular genetic testing is complicated by the wide spectrum of mutations that aknown to cause GCPS. Current methodology includes the following:  

a.  Sequence analysis 

b.  Loss-of-heterozygosity (LOH) analysis to detect large deletions c.  qPCR  

d.  Array CGH 

References: 

GeneReviews. (2005). Seattle, WA: University of Washington. Available :

http://www.ncbi.nlm.nih.gov/books/NBK51784/

Greig cephalopolysyndactyly syndrome - Genetics Home Reference. (n.d.). Retrieved September 23, 2013, from

http://ghr.nlm.nih.gov/condition/greig-cephalopolysyndactyly-syndrome

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HOLOPROSENCEPHALY

IntroductionHoloprosencephaly is a disorder caused by the failure of the prosencephalon (the embryonic forebrain)

sufficiently divide into the double lobes of the cerebral hemispheres. The result is a single-lobed brain structure ansevere skull and facial defects. In most cases of holoprosencephaly, the malformations are so severe that babies d

 before birth. In less severe cases, babies are born with normal or near-normal brain development and facideformities that may affect the eyes, nose, and upper lip.There are three classifications of holoprosencephaly. Alobar,  in which the brain has not divided at all,

usually associated with severe facial deformities. Semilobar, in which the brain's hemispheres have somewh

divided, causes an intermediate form of the disorder. Lobar, in

which there is considerable evidence of separate brainhemispheres, is the least severe form. In some cases of lobar

holoprosencephaly the baby's brain may be nearly normal.

The least severe of the facial anomalies is the median cleft

lip ( premaxillary agenesis). The most severe is cyclopia, anabnormality characterized by a single eye located in the area

normally occupied by the root of the nose, and a missing nose or a proboscis (a tubular-shaped nose) located above the eye. The leastcommon facial anomaly is ethmocephaly,in which a proboscis

separates closely-set eyes. Cebocephaly,  another facial anomaly,

is characterized by a small, flattened nose with a single nostril

situated below incomplete or underdeveloped closely-set eyes.

Genetic Factors

Mutations in 11 genes have been found to cause nonsyndromic holoprosencephaly. These genes providinstructions for making proteins that are important for normal embryonic development, particularly for determinin

the shape of the brain and face. About 25 percent of people with nonsyndromic holoprosencephaly have a mutatio

in one of these four genes: SHH , ZIC2, SIX3, or TGIF1. Mutations in the other genes related to nonsyndromholoprosencephaly are found in only a small percentage of cases. Many individuals with this condition do not hav

an identified gene mutation. The cause of the disorder is unknown in these individuals.

The brain normally divides into right and left hemispheres during the third to fourth week of pregnancy. T

establish the line that separates the two hemispheres (the midline), the activity of many genes must be tightregulated and coordinated. These genes provide instructions for making signaling proteins, which instruct the celwithin the brain to form the right and left hemispheres.

Signaling proteins are also important for the formation of the eyes. During early development, the cells th

develop into the eyes form a single structure called the eye field. This structure is located in the center of th

developing face. The signaling protein produced from the SHH   gene causes the eye field to separate into tw

distinct eyes. The SIX3 gene is involved in the formation of the lens of the eye and the specialized tissue at the bacof the eye that detects light and color (the retina).

Mutations in the genes that cause nonsyndromic holoprosencephaly lead to the production of abnormal

nonfunctional signaling proteins. Without the correct signals, the eyes will not form normally and the brain donot separate into two hemispheres. The development of other parts of the face is affected if the eyes do not move t

their proper position. The signs and symptoms of nonsyndromic holoprosencephaly are caused by abnorm

development of the brain and face.

Researchers believe that other genetic or environmental factors, many of which have not been identifie play a role in determining the severity of nonsyndromic holoprosencephaly.

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EpidemiologyHoloprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births. This is like

to be an underestimation owing to recognition of milder cases later in life.

Holoprosencephaly occurs worldwide. Reported frequency rates of holoprosencephaly have wide variationdepending on the study design. The rates are higher if terminations of pregnancy are included. The frequenc

among all pregnancies has been reported to be 1 in 250 based on a study on embryos obtained through induce

abortion, making this the most common human forebrain malformation.

Ethnic variations have been reported, with a higher birth prevalence among Far East Asians and Filipinothan in whites in Hawaii and among Pakistanis in Midlands.

 However, these may be due to lower prenatal detectio

rates in these groups and hence lower rates of pregnancy terminations. Holoprosencephaly has been reported to b

more common in females than in males.

Diagnostic ProceduresImaging of the brain by CT scan or (preferably) MRI confirms the diagnosis of HPE, may define th

anatomic subtype, and identifies associated CNS anomalies. Approximately 25%-50% of individuals with HP

have a numeric or structural chromosomal abnormality detectable by chromosome analysis. Approximately 18%

25% of individuals with monogenic HPE have a recognizable syndrome and the remainder have nonsyndromHPE. Molecular genetic testing is possible for many of the genes associated with nonsyndromic HP

Approximately 10% of individuals with HPE have defects in cholesterol biosynthesis.

References:

GeneReviews. (2005). Seattle, WA: University of Washington. Available :

http://www.ncbi.nlm.nih.gov/books/NBK51784/

 Nonsyndromic holoprosencephaly - Genetics Home Reference. (n.d.). Retrieved September 34, 2013, fromhttp://ghr.nlm.nih.gov/condition/nonsyndromic-holoprosencephaly

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LIPOAMIDE DEHYDROGENASE DEFICIENCY (LDD)

Introduction

The DLD  gene provides instructions for making a protein called dihydrolipoamide dehydrogenase. Th

 protein is a part (a subunit) of several enzyme complexes (groups of enzymes that work together). Thecomplexes are essential for the breakdown of certain molecules to produce energy in cells. Dihydrolipoamid

dehydrogenase forms a subunit called the E3 component that is shared by several enzyme complexes.

Branched-chain alpha-keto acid dehydrogenase, or BCKD, is one of the enzyme complexes that include th

E3 component. The BCKD enzyme complex performs one step in the normal breakdown of three protein buildin blocks (amino acids). These amino acids — leucine, isoleucine, and valine — are obtained from the diet. They a

 present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. The breakdown

these amino acids produces molecules that can be used for energy.

The E3 component is also part of the pyruvate dehydrogenase complex. This enzyme complex plays a

important role in the production of energy for cells. It converts a molecule called pyruvate, which is formed fromthe breakdown of carbohydrates, into another molecule called acetyl-CoA. The E3 component performs one part

this chemical reaction. The conversion of pyruvate is essential to begin the series of chemical reactions th

 produces adenosine triphosphate (ATP), the cell's main energy source.

The symptoms of dihydrolipoamide dehydrogenase are highly variable and depend on the DLD mutation —even cases caused by two G229C mutations are variable. For some affected individuals with two G229C mutation

fatigue after exercise may be the only symptom and the condition may go unnoticed until adulthood. In other case

symptoms may present in infancy and be severe: recurrent attacks of vomiting, poor muscle tone, poor reflexelistlessness, enlarged liver, and seizures. Individuals with two G229C mutations tend to have milder symptom

than individuals with one G229C mutation in conjunction with another mutation in the DLD  gene. 

Genetic Factors

Dihydrolipoamide dehydrogenase deficiency is an autosomal recessive disease caused by mutations

the DLD gene. An individual who inherits one mutation is a ―carrier‖ and is not expected to have related heal problems. An individual who inherits two mutations in the DLD gene, one from each parent, is expected to b

affected with DLD. If both members of a couple are carriers, the risk for an affected child is 25% in eac

 pregnancy; therefore, it is especially important that the reproductive partner of a carrier be offered testing.

Epidemiology

DLD is a rare disorder most frequently reported in individuals of Ashkenazi (Eastern European) Jewis

ancestry but occurring in other populations as well. The carrier frequency of DLD in the Ashkenazi Jewi

 population is approximately 1/107. Having a relative who is a carrier or is affected can also increase an individual

risk to be a carrier. Consultation with a genetics health professional may be helpful in determining carrier risk an

appropriate testing. If a gene mutation is identified, an individual should speak to a physician or genetics healt professional about the implications of the result and appropriate testing for the reproductive partner and at-ri

family members.

Diagnostic ProceduresDue to the rarity of the disease, there is no established means of diagnosing the condition. Genetic testing

can reveal if parents are the carrier of the disease. Children are often diagnosed based on a combination of family

history, parental genetic testing and blood tests.Blood tests are often used to diagnose dihydrolipoamide dehydrogenase deficiency. Since dihydrolipoamide

dehydrogenase deficiency causes the inability to metabolize certain amino acids, high levels of these amino acids in the blooare indicative of the deficiency. In addition, the blood may have high lactate and episodes of low glucose levels and analysisof the urine may show a distinct profile of organic acids. Furthermore, genetic testing for DLD mutations is available.  

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References:

 Dihydrolipoamide Dehydrogenase Deficiency Inherited Condition - 23andMe. (n.d.). Retrieved September 22,

2013, from https://www.23andme.com/health/dihydrolipoamide-dehydrogenase-deficiency/howitworks/

GeneReviews. (2005). Seattle, WA: University of Washington. Available :

http://www.ncbi.nlm.nih.gov/books/NBK51784/

McKusick VA and Kniffin CL. Dihydrolipoamide dehydrogenase. OMIM  Available

at:http://omim.org/entry/248600. 

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PALLISTER-HALL SYNDROME (PHS)

Introduction

Pallister-Hall syndrome is a disorder that affects the development of many parts of the body. Most peop

with this condition have extra fingers and/or toes (polydactyly), and the skin between some fingers or toes may b

fused (cutaneous syndactyly). An abnormal growth in the brain called a hypothalamic hamartoma is characterist

of this disorder. In many cases, these growths do not cause any medical problems; however, some hypothalamhamartomas lead to seizures or hormone abnormalities that can be life-threatening in infancy. Other features o

Pallister-Hall syndrome include a malformation of the airway called a bifid epiglottis, an obstruction of the an

opening (imperforate anus), and kidney abnormalities. Although the signs and symptoms of this disorder vary fromild to severe, only a small percentage of affected people have serious complications.

Genetic Factors

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene each cell is sufficient to cause the disorder. In some cases, an affected person inherits a mutation in theGLI3 gen

from one affected parent. Other cases result from new mutations in the gene and occur in people with no history othe disorder in their family.

Mutations in the GLI3 gene cause Pallister-Hall syndrome.The GLI3 gene provides instructions for makina protein that controls gene expression, which is a process that regulates whether genes are turned on or off

 particular cells. By interacting with certain genes at specific times during development, the GLI3 protein plays

role in the normal shaping (patterning) of many organs and tissues before birth.

Mutations that cause Pallister-Hall syndrome typically lead to the production of an abnormally shoversion of the GLI3 protein. Unlike the normal GLI3 protein, which can turn target genes on or off, the sho

 protein can only turn off (repress) target genes. Researchers are working to determine how this change in th

 protein's function affects early development. It remains uncertain how GLI3  mutations can cause polydactyl

hypothalamic hamartoma, and the other features of Pallister-Hall syndrome.

Epidemiology

This condition is very rare; its prevalence is unknown.

Diagnostic Procedures

The diagnosis of Pallister-Hall syndrome is based on family history and the clinical findings hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus, and ren

abnormalities. GLI3 is the only gene in which mutations are known to cause Pallister-Hall syndrome. Pallister-Ha

syndrome (PHS) can be diagnosed based on clinical findings in individuals with classic signs. Molecular genet

testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis

individuals in whom the clinical findings are ambiguous or mild.Major findings are the following:

  Hypothalamic hamartoma, a non-enhancing mass in the floor of the third ventricle posterior to the optchiasm that is isointense to grey matter on T1 and T2 pulse sequences of an MRI, but may have distin

intensity on FLAIR (Neither cranial CT examination nor cranial ultrasound examination is adequate f

diagnosis of hypothalamic hamartoma.)

  Mesoaxial (i.e., insertional or central) polydactyly, the presence of six or more well-formed digits with

'Y'-shaped metacarpal or metatarsal bone

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  Postaxial polydactyly (PAP) types A and B. PAP-A is the presence of a well-formed digit on the ulnar ofibular aspect of the limb. PAP-B is the presence of a rudimentary digit or nubbin in the same locatio

Postaxial polydactyly is probably more common than mesoaxial polydactyly; however, the nonspecifici

of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of centr

African descent require caution in its use as a diagnostic feature.

  Bifid epiglottis, a midline anterior-posterior cleft of the epiglottis that involves at least two thirds of th

epiglottic leaf. It is a useful feature for clinical diagnosis because it appears to be very rare in syndromother than PHS and is also rare as an isolated malformation.

  Other. Imperforate anus, renal abnormalities including cystic malformations, renal hypoplasia, ectop

ureteral implantation, genitourinary anomalies including hydrometrocolpos, pulmonary segmentatio

anomalies including bilateral bilobed lungs, and non-polydactyly skeletal anomalies including short limbs

The diagnosis is established in the following individuals:

  A proband if mesoaxial polydactyly and hypothalamic hamartoma are present

  The first-degree relative of a proband if hypothalamic hamartoma or central or postaxial polydactyly a

 present (Postaxial polydactyly type B can be used as a diagnostic criterion for first-degree relatives only

 persons who are not of central African descent.)

Individuals with postaxial (but not mesoaxial) polydactyly and a hypothalamic hamartoma or mesoaxi

 polydactyly without hypothalamic hamartoma or hypothalamic hamartoma and other non-polydacty

malformations should be considered for GLI3sequencing.

References:

Azzam A, Lerner DM, Peters KF, Wiggs E, Rosenstein DL, Biesecker LG. Psychiatric and neuropsychologicalcharacterization of Pallister-Hall syndrome. Clin Genet. 2005 Jan;67(1):87-92. 

GeneReviews. (2005). Seattle, WA: University of Washington. Available :http://www.ncbi.nlm.nih.gov/books/NBK51784/

 Pallister-Hall syndrome - Genetics Home Reference. (n.d.). Retrieved September 21, 2013, from

http://ghr.nlm.nih.gov/condition/pallister-hall-syndrome 

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ARGININOSUCCINICACIDURIA

IntroductionArgininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood.

Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. Th

nervous system is especially sensitive to the effects of excess ammonia.

Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant withargininosuccinic aciduria may be lacking in energy (lethargic) or unwilling to eat, and have poorly controlled

 breathing rate or body temperature. Some babies with this disorder experience seizures or unusual body

movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delayand intellectual disability. Progressive liver damage, skin lesions, and brittle hair may also be seen.

Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the

 bloodstream only during periods of illness or other stress.

Genetic FactorsThis condition is inherited in an autosomal recessive pattern, which means both copies of the gene in eac

cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of thmutated gene, but they typically do not show signs and symptoms of the condition.

Mutations in the ASL gene cause argininosuccinic aciduria. Argininosuccinic aciduria belongs to a class

genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occur in liver cells.  processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that

excreted by the kidneys.

In argininosuccinic aciduria, the enzyme that starts a specific reaction within the urea cycle is damaged missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form

ammonia.

Ammonia is especially damaging to the nervous system, so argininosuccinic aciduria causes neurologic

 problems as well as eventual damage to the liver.

EpidemiologyArgininosuccinic aciduria occurs in approximately 1 in 70,000 newborns.

Diagnostic Procedures

Elevated plasma ammonia concentration (>150 µmol/L, sometimes up to ≥2000-3000 µmol/L), elevat plasma citrulline concentration (usually 200-300 µmol/L), and elevated argininosuccinic acid in the plasma or uri

establish the diagnosis of ASL deficiency. Molecular genetic testing of ASL (the only gene in which mutations a

known to be causative) and assay of ASL enzyme activity may be helpful when the biochemical findings ar

equivocal. Note: All 50 states in the US include ASL deficiency in their  newborn screening programs.

References:

 Argininosuccinic aciduria - Genetics Home Reference. (n.d.). Retrieved September 21, 2013, from

http://ghr.nlm.nih.gov/condition/argininosuccinic-aciduria 

GeneReviews. (2005). Seattle, WA: University of Washington. Available :

http://www.ncbi.nlm.nih.gov/books/NBK51784/ 

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INFANTILE REFSUM DISEASE (IRD)

Introduction

Infantile Refsum disease (IRD) is a medic

condition within the Zellweger spectrum of perixisom

 biogenesis disorders (PBDs), inherited genetic disordethat damage the white matter of the brain and affe

motor movements. PBDs are part of a larger group

disorders called the leukodystrophies. The Zellweg

spectrum of PBDs include related, but not more severdisorders referred to as Zellweger syndrome (ZS) an

neonatal adrenoleukodystrophy. Collectively, the

disorders are caused by inherited defects in any one of

genes, called PEX genes, which are required for thnormal formation and function of peroxisome

Peroxisomes are cell structures required for the normformation and function of the brain, eyes, liver, kidneyand bone. They contain enzymes that break down tox

substances in the cells, including very long chain fatty acids and phytanic acid (a type of fat found in certa

foods), and synthesize certain fatty materials (lipids) that are required for cell function. When peroxisomes are n

functioning, there is over-accumulation of very long chain fatty acids and phytanic acid, and a lack of bile aciand plasmalogens--specialized lipids found in cell membranes and the myelin sheaths and encase and protect nerv

fibers. IRD has some residual perixisome function, resulting in less severe disease than in Zellweger syndrom

Symptoms of IRD begin in infancy with retinitis pigmentosa, a visual impairment that oft en leads to blindnesand hearing problems that usually progress to deafness by early childhood. Other symptoms may include rapi

 jerky eye movements (nystagmus); floppy muscle tone (hypotonia) and lack of muscle coordination (ataxia

mental and growth disabilities; abnormal facial features; enlarged liver; and white matter abnormalities of bra

myelin. At the mildest extreme of the disorder, intellect may be preserved. Although Adult Refsum disease anIRD have similar names, they are separate disorders caused by different gene defects.

Genetic FactorsInfantile Refsum disease is an autosomal recessive disorder due to phytanic oxidase deficiency as a result

mutations in PEX genes 1, 2, and 26. As yet, the exact gene mutation in the Amish has not been identified and only ofamily, in Northern Indiana, has been reported. Loci may be at 8q21.1, 7q21-q22, and 22q11.21 

EpidemiologyRefsum disease is rare, with just 60 cases published worldwide.

In patients who are untreated or diagnosed late, severe neurological impairment, wasting, and depressiodevelop, subsequently leading to a high mortality rate. Attenuation of neurologic, ophthalmologic, and cardia

symptoms requires constant adherence to a suitable diet and plasmapheresis.

 No racial predominance is reported.

Only male cases were reported initially; however, now, neither sex predominates.

Classic Refsum disease manifests in children aged 2-7 years; however, diagnosis usually is delayed unt

early adulthood. Infantile Refsum disease makes its appearance in early infancy.

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Diagnostic ProceduresThe diagnosis of Refsum disease is suspected on the basis of clinical findings and established by a plasm

 phytanic acid concentration greater than 200 µmol/L in most affected individuals. Other biochemical findin

include increased phytanic acid/pristanic acid ratio, elevated pipecolic acid concentrations (in 20% of affecteindividuals), and deficiency of phytanoyl-CoA hydroxylase enzyme activity or deficiency of the peroxisom

targeting signal type 2 receptor. Mutations in two genes have been identified in individuals with Refsu

disease: PHYH , the gene that encodes phytanoyl-CoA hydroxylase, is mutated in more than 90%

individuals; PEX7 , the gene that encodes the PTS2 receptor, is mutated in fewer than 10% of individuals.  

References:

Bader, P.I., Dougherty, S., Cangany, N., Raymond, G., and Jackson, C.E.: Infantile Refsum disease in four Amissibs. Am. J. Med. Genet. 90: 110-114, 2000.

GeneReviews. (2005). Seattle, WA: University of Washington. Available :

http://www.ncbi.nlm.nih.gov/books/NBK51784/ 

 Infantile Refsum Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS).(n.d.). Retrieved September 22, 2013, from

http://www.ninds.nih.gov/disorders/refsum_infantile/refsum_infantile.htm

Wanders, R.J., Schutgens, R.B., Schrakamp, G, van den Bosch, H., Tager, J.M., Schram, A.W., Hashimoto, T.,

Poll-The, B.T., and Saudubrau, J.M.: Intantile Refsum disease: deficiency of catalases-containing particle

(peroxisomes), alkyldihydroxyacetone phosphate synthase and peroxisomal beta-oxidation enzyme proteins. Eur. J. Pediatr. 145: 172-175, 1986.

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ZELLWEGER SYNDROME

IntroductionThe Zellweger spectrum is a group of conditions that hav

overlapping signs and symptoms and affect many parts of the bod

This group of disorders includes Zellweger syndrome, neonat

adrenoleukodystrophy (NALD), and infantile Refsum disease. Theconditions were once thought to be distinct disorders but are noconsidered to be part of the same disease spectrum. Zellweg

syndrome is the most severe form of the Zellweger spectrum, NALD

intermediate in severity, and infantile Refsum disease is the least seveform. In some cases, it can be difficult to distinguish between the thr

conditions that make up the Zellweger spectrum.

Individuals with Zellweger syndrome develop signs an

symptoms of the condition during the newborn period. These infanexperience weak muscle tone (hypotonia), feeding problems, hearin

loss, vision loss, and seizures. These pro  blems are caused by th

degeneration of myelin, which is the covering that protects nerves an promotes the efficient transmission of nerve impulses. The part of th

 brain and spinal cord that contains myelin is called white matte

Destruction of the myelin (demyelination) leads to loss of white matt

(leukodystrophy). Children with Zellweger syndrome also develop lifthreatening problems in other organs and tissues, such as the live

heart, and kidneys. They may have skeletal abnormalities, including

large space between the bones of the skull (fontanels) and characterist bone spots known as chondrodysplasia punctata that can be seen with an x-ray. Affected individuals hav

distinctive facial features, including a flattened face, broad nasal bridge, and high forehead. Children wi

Zellweger syndrome typically do not survive beyond the first year of life.

People with NALD or infantile Refsum disease have more variable features than those with Zellwegsyndrome and usually do not develop signs and symptoms of the disease until late infancy or early childhood. The

may have many of the features seen in more severely affected individuals; however, their condition typical

 progresses more slowly. Children with these less severe conditions often have hypotonia, vision problems, hearinloss, liver dysfunction, developmental delay, and some degree of intellectual disability. Most people with NALsurvive into childhood, and those with infantile Refsum disease may reach adulthood. In rare cases, individuals

the mildest end of the Zellweger spectrum have developmental delay in childhood and hearing loss or visio

 problems beginning in adulthood.

Genetic Factors

Mutations in 12 genes have been found to cause the Zellweger spectrum. These genes provide instruction

for making a group of proteins known as peroxins, which are essential for the formation and normal functioning ocell structures called peroxisomes. Peroxisomes are sac-like compartments that contain enzymes needed to brea

down many different substances, including fatty acids and certain toxic compounds. They are also important for th

 production of fats (lipids) used in digestion and in the nervous system. Peroxins assist in the formation (biogenesiof peroxisomes by producing the membrane that separates the peroxisome from the rest of the cell and b

importing enzymes into the peroxisome.

Mutations in the genes that cause the Zellweger spectrum prevent peroxisomes from forming normallDiseases that disrupt the formation of peroxisomes, including the Zellweger spectrum, are called peroxisom

 biogenesis disorders. If the production of peroxisomes is altered, these structures cannot perform their usu

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functions. The signs and symptoms of Zellweger syndrome are due to the absence of functional peroxisomes withcells. NALD and infantile Refsum disease are caused by mutations that allow some peroxisomes to form.

Mutations in the PEX1 gene are the most common cause of the Zellweger spectrum and are found in near

70 percent of affected individuals. The other genes associated with the Zellweger spectrum each account for

smaller percentage of cases of this condition.

EpidemiologyZellweger syndrome is a fatal autosomal recessive disorder. The Zellweger spectrum is estimated to occ

in 1 in 50,000 individuals.

Diagnostic ProceduresThe diagnosis can be definitively determined by biochemical assays. Biochemical abnormalities detected

 blood and/or urine should be confirmed in cultured fibroblasts. Measurement of plasma very-long-chain fatty ac

(VLCFA) levels is the most commonly used and most informative initial screen. Elevation of C26:0 and C26:1 anthe ratios C24/C22 and C26/C22 is consistent with a defect in peroxisomal fatty acid metabolism. Mutations

twelve different PEX genes ( PEX1, PXMP3 [ PEX2], PEX3, PEX5, PEX6 , PEX10, PEX12, PEX13, PEX14

 PEX16 , PEX19, and PEX26 ) —  those that encode peroxins, the proteins required for normal peroxisome assemb —  have been identified in PBD, ZSS. Mutations in PEX1, the most common cause of PBD, ZSS, are observed about 68% of  affected individuals. . 

References:

GeneReviews. (2005). Seattle, WA: University of Washington. Available :

http://www.ncbi.nlm.nih.gov/books/NBK51784/ 

 Zellweger spectrum - Genetics Home Reference. (n.d.). Retrieved September 22, 2013, fromhttp://ghr.nlm.nih.gov/condition/zellweger-spectrum