Lethal Syndrome of Skeletal Dysplasia andProgressive Central Nervous System Degeneration

Mahvash Khosravi,1 David D. Weaver,1* Marilyn J. Bull,2 Ralph Lachman,3 and David L. Rimoin4

1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana2Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana3Departments of Radiology and Pediatrics, Harbo-UCLA Medical Center, UCLA School of Medicine ,Los Angeles, California

4Department of Pediatrics and Medical Genetics—Birth Defects Center, Cedars-Sinai Medical Center,Los Angeles, California

We describe 3 sibs (2 males and 1 female)with multiple congenital anomalies, poorgrowth, seizures, and progressive centralnervous system (CNS) degeneration leadingto death in infancy. Radiographic changesin all 3 were similar, and included moderateshortness of long bones, platyspondyly, andhypoplastic pelvis. Autopsies showed dif-fuse encephalomyelopathy and enlarge-ment of the lateral and third ventricles. Ly-sosomal enzyme activities were normal. Col-lagen type II analysis on 2 of the sibsindicated normal collagen. Chromosomesappeared normal. Even though the radio-graphic and chondroosseous morphologicfindings in these sibs have a certain similar-ity to Dyggve-Melchior-Clausen syndrome,their clinical course does not fit this condi-tion. These infants appear to represent anew syndrome of bone dysplasia and CNSdegeneration inherited as an autosomal re-cessive trait. Am. J. Med. Genet. 77:63–71,1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: autosomal recessive; bonedysplasia; central nervoussystem degeneration; birthdefects; seizures

INTRODUCTION

We present in this paper a previously apparently un-recognized syndrome consisting of a bone dysplasia

with rapid central nervous system (CNS) degenerationwhich led to the death during infancy of 3 affected sibs.The radiographic findings and chondroosseous mor-phology in this condition are similar to those of Dyggve-Melchior-Clausen syndrome, while the rapid CNS de-terioration is not. The condition appears to be an au-tosomal recessive trait.

CLINICAL REPORTS

The findings in the 3 affected sibs are presented inTable I and Figures 1–14.

Case 1

The first of the 4 sibs was a boy (family 82883) bornat 35 weeks of age of an otherwise normal gestation.The parents, a 19-year-old mother and a 35-year-oldfather, were married, healthy and non-consanguineous.The pregnancy was complicated by polyhydramnios.The patient was born spontaneously. Apgar scoreswere 8 and 9 at 1 and 5 minutes, respectively. Theinfant had a birth weight of 3,390 g (50th centile),length of 52 cm (5th centile), and occipitofrontal cir-cumference (OFC) of 34 cm (30th centile). He was dis-charged from the hospital at age 3 days. The dischargesummary reported no neonatal problems or physicalabnormalities. Subsequently, he experienced poorgrowth and developmental delay, and had severe sei-zures.

At 5 months, he had a length of 47.8 cm (<3rd cen-tile), weight of 3.2 kg (<3rd centile), and OFC of 35.7 cm(−5 S.D.). On examination he had a fingertip-size an-terior fontanel, overfolding of the superior and poste-rior helicies on the right, short limbs, and simiancreases. He did not have a depressed nasal bridge ormidface hypoplasia. Radiographic evaluation showed anormal skull with no ossification defects (Fig. 1). Theclavicles were elongated (Fig. 1). The long bones of thelimbs were all considerably shortened, and except forsome irregularities of the proximal humeral metaphy-ses, the epiphyses and metaphyses appeared normal(Fig. 1). The radii and ulnae were hypoplastic. Therewas generalized brachydactyly. In addition, marked

Contract grant sponsor: NIH; Contract grant number: HD-22657-10.

*Correspondence to: David D. Weaver, M.D., Department ofMedical and Molecular Genetics, Indiana University School ofMedicine, 975 West Walnut Street, Indianapolis, IN 46202-5251.E-mail: dweaver@medgen.iupui.edu

Received 26 December 1996; Accepted 3 October 1997

American Journal of Medical Genetics 77:63–71 (1998)

© 1998 Wiley-Liss, Inc.

platyspondyly with wafer-thin vertebral bodies werenoted (arrows, Figs. 1 and 2). The pelvis was underde-veloped with irregular calcification around the outerportion of the iliac wings, and there were a widenedsacrosciatic notch and a trident configuration to theacetabulum (Fig. 2). The roofs of the acetabula werequite hypoplastic. A head computerized tomography(CT scan) showed enlarged ventricles and prominentextracerebral fluid collections (Fig. 3). The infant diedat the age of 5 months from respiratory failure due topoor CNS function. The karyotype was normal (46,XY).Urine amino acids levels, and serum and white celllysosomal hydrolases were all normal. Autopsy demon-strated hypoplasia of the white matter and a small cer-ebellum.

Case 2

The parents’ second child, a male, is normal in allrespects. The third sib, a girl and the second affectedchild, was the product of an uncomplicated, term preg-nancy without prenatal care. Birth was spontaneouswith Apgar scores of 1, 4, and 7 at 1, 5, 10 minutes,respectively. Immediately following birth, the infantrequired resuscitation by supplemental oxygen. Thecause of the depression at birth was not determined.She had a birth weight of 2,443 g (5th centile), a lengthof 39 cm (<3rd centile), and an OFC of 34 cm (50thcentile).

For the next 14 days, she was in a neonatal intensivecare unit where she required supplemental nasal oxy-gen for low blood oxygen saturations and persistent

tachypnea. She was discharged from a local hospital onsupplemental nasal oxygen. At 17 days, she was admit-ted to Riley Hospital for Children because of persistentsupplemental oxygen requirement and for evaluationof a skeletal dysplasia. Her physical findings at thattime included a flat face, sparse eyebrows and lashes,short and upturned nose with a prominent glabella,depressed nasal bridge, long philtrum (Figs. 4 and 5),abnormally shaped pinnae with stenosis of the externalauditory canals, short neck, a small thorax, short upperand lower limbs with dislocated elbows, curved fore-arms, ulnar deviation of the hands, simian creases,prominent flexion creases in the hands, and short fin-gers and toes. In addition, she had marked fragility ofscalp hair which, on microscopic examination, showedsplayed edges and no polarization. The hair findingswere thought to represent trichorrhexis nodosa. Shedid not have a palate cleft, her genitalia were normal,and she had no focal abnormal neurologic signs. Herweight, length, and OFC were 2,440 g (<3rd centile), 41cm (3rd centile) and 35.5 cm (50th centile), respec-tively. Radiographic findings were similar to those ofher brother, and included shortness and hypoplasia of

TABLE I. Clinical and Laboratory Manifestations of 3 AffectedSibs, and Dyggve-Melchior-Clausen Syndrome

I II IIIDMCg

syndrome

Sex M F M DAGestational age (weeks) 35 38 38 DAFailure to thrive/short stature +a + + +Flat face −b + + −Depressed nasal bridge − + + −Short and upturned nose + + + −Short neck + + + +Small thorax + + + +Brachydactyly + + + +Hypoplastic pelvis + + + +Short limbs + + + +Simian creases + + + ?c

Renal abnormality − − + −Platyspondyly with

wafer-thin vertebral bodies + + + −Seizures + + + −Progressive neurologic

deterioration + + + −Age at death (months) 5.5 5 3.5 DAf

Urine amino and organicacid levels Ne N N −

White cell lysosomalhydrolases N N Od −

a+, finding present.b−, finding absent.c?, unknown.d O, test not done.eN, normal test result.fDA, does not apply.g DMC, Dyggve-Melchior-Clausen syndrome.

Fig. 1. Radiograph of patient 1 at age 5 months. Note skull with noossification defects, elongated clavicles, and short long bones, and markedplatyspondyly (arrow).

64 Khosravi et al.

all long bones, bowing of radii and ulnae (Fig. 6), wafer-thin and poorly calcified vertebral bodies (Figs. 7 and8), hypoplastic pelvis with marked irregularities in cal-cification of the outer iliac wings, widened sacrosciaticnotch, trident configuration of the acetabula, andmarked hypoplasia of the acetabular roofs (Fig. 7). Theclavicles were elongated (Fig. 7). The metaphyses werenormal except in the proximal humeral regions wherethey were irregular (Fig. 7). A head and cervical spine

magnetic resonant imaging (MRI) at age 17 days indi-cated a normal brain (Fig. 9) except for kinking andnarrowing of the caliber of the spinal cord at the cer-vical-medullary junction. However, the patient had nosymptoms from these latter abnormalities.

During her 46 days of hospitalization, the patientcontinued to have a persistent supplemental oxygenrequirement. A polysomnogram at age 19 days showedborderline blood oxygen saturation on room air, but didnot demonstrate apnea from either a central or ob-structive source. A repeat polysomnogram performed 1month later showed that a 1-liter-per-minute oxygensupplementation was needed to maintain blood normaloxygen saturations. The oxygen requirement was be-lieved to be due to restrictive lung disease. During thishospitalization a urine screen for genetic disorders thatincluded organic and amino acids was normal exceptfor an elevated glycine level on electrophoresis. Shewas discharged with supplemental oxygen.

At age 2 1/2 months she was seen as an outpatient.During this visit she was able to recognize her mother’svoice and fixate briefly with her eyes. At age 3 months,her mother found her cyanotic and gasping for air. Shewas readmitted to the hospital and remained there un-til her death. The day following her admission she re-quired tracheal intubation and mechanical ventilation

Fig. 3. A head CT scan of patient 1 at age 5 months. Note atrophy,enlarged ventricles, and prominent extracerebral fluid collection.

Fig. 2. Radiograph of patient 1 at age 5 months. Note hypoplastic pubicbones and irregularly calcified iliac wings, widened sacrosciatic notch anda trident configuration of the acetabulum. Arrow points out platyspondyly.

Fig. 4. Anterior view of total body of patient 2 at age 17 days. Note flatmidface, curved forearms, short fingers, and rhizomelic shortness of upperand lower limbs.

New Bone Dysplasia With CNS Degeneration 65

for progressive respiratory distress. Two weeks later, atracheostomy was performed. Subsequently, she couldnot be weaned from the ventilator because of progres-sive central nervous system degeneration, and she diedat age 5 months.

During this hospitalization, she experienced recur-rent seizures that were unresponsive to anticonvulsantmedications. Electroencephalograms (EEG) were ab-normal and showed mild to moderate diffusely slowwaves, and independent multifocal spike-wave dis-charges, the latter arising from multiple loci over bothcerebral hemispheres. She also had chronic carbon di-oxide retention and a metabolic acidosis. When 4months old, a repeat urine screen for genetic disordersindicated 2+ proteinuria, 4+ generalized aminoaciduriaand lacticaciduria with the lactate level being 280mmol/mol (normal 31–65 mmol/mol). The metabolicacidosis and urinary findings were thought to be due toproximal and distal renal tubular acidosis. She alsohad recurrent anemia that required frequent transfu-sions. Because of feeding difficulties and esophagealreflux, she had a Nissen fundoplication and placementof a gastric feeding tube. Also during this hospitaliza-tion, she had the onset of marked and generalizededema which did not respond to intravascular albumininfusions nor treatment with furosemide (LasixR).

A CT scan of the head (Fig. 10) at age 3 monthsshowed marked cortical loss in the cerebral and cer-ebellar areas, ventriculomegaly, enlargement of thesubarachnoid spaces over the whole brain includingthe posterior fossa, and lack of normal gray and whitematter differentiation. In addition the foramen mag-num, although smaller than normal, was found to beconsiderably larger than the brainstem. There was noevidence of brainstem compression or loss of normalsubarachnoid space in the cervical vertebrae scanned.The neural arches also were reduced in size. Other

tests done at this time included a brainstem auditoryevoked responses (BAERs) and a somatosensoryevoked responses (SERs); the latter was obtained byposterior tibial nerve stimulation. Both tests were ab-normal with the former showing absence of responsesfollowing wave II on the right and wave I on the left,and the latter by absence of consistent scalp responsesfollowing peripheral stimulation. These findings wereconsistent with brain dysfunction. Chromosome find-ings were normal (46,XX). Serum and white cell lyso-somal hydrolase activities also were normal.

Autopsy demonstrated ventricular hypertrophy ofthe heart. The lungs were congested and had atelecta-sis, but not hypoplastic. Uterus and Fallopian tubeswere diminutive. The brain, including the cerebellum,was atrophic in all areas, and the ventricles were en-larged. On histologic examination, there was extremedeficiency of all cellular elements, degeneration of mosttracts, and marked cavitation of the white matter inthe frontal lobes. Cartilage histology showed a growthplate that in some places had regular morphology. Inother areas, the growth plate contained short columns

Fig. 6. Radiograph of patient 2 at age 3 weeks. Note the short longbones and bowing of the radii and ulnae.

Fig. 5. Side view of patient 2 at age 17 days. Note sparse eyebrows andlashes, short upturned nose and depressed nasal bridge, long philtrum,and abnormally shaped pinnae.

66 Khosravi et al.

of chondrocytes with hypocellular, fibrous-appearingmatrix. At the iliac crest there was overgrowth of un-usual appearing bone at the periphery of the growthplate. The resting cartilage was very abnormal withunusual distribution of the cells. These cells were fre-quently hemispherical or crescent-shaped, and oftenformed small circular clusters positioned in unusuallooking matrix. The chondrocytes themselves con-tained inclusion bodies. There was no degeneration ofthe cartilage. Collagen analysis indicated normal typeII collagen.

Case 3

The fourth offspring and third affected sib was a boy.The pregnancy with this child was complicated by poly-hydramnios and abnormal sonographic findings. Alevel II ultrasound at gestational age (GA) of 17 weeksfound no shortness of limbs (mean GA by ultrasound 417.4 weeks; femoral length 4 16.9 weeks [range ±2S.D. 4 15.3 − 8.4 weeks]) or other fetal abnormalities.At GA 22 weeks, a repeat ultrasound study found thelimb lengths to be near −2 S.D. By 27 weeks of gesta-tion, the limbs were clearly short with the femorallength equivalent to 22.4 weeks (±2 S.D. 4 20.5 − 24.3weeks), and there was marked polyhydramnios. Repeat

ultrasound evaluations at 29 and 33 weeks verifiedthese findings. The delivery occurred spontaneously atthe 38th week of gestation without complications.Birth weight was 2,370 g (<3rd centile), length 40 cm(<3rd centile), and OFC 34.5 cm (35th centile). His Ap-gar scores were 1 at 1 minute and 6 at 5 minutes. Hehad a heart rate of less than 100/min and poor respi-ratory effort. He was treated with supplemental oxy-gen, and bag and mask ventilation. Physical examina-tion at birth showed prominent eyes, upturned nose,depressed nasal bridge, flat midface, micrognathia,short neck, a small chest (maximum chest circumfer-ence 4 29 cm [5th centile]), short limbs, simiancreases, brachydactyly, dimples over the ankles, gen-eralized cutis marmorata, and sparse hair. He had anormal palate. Genitalia were normal but testes wereundescended. The patient is shown at age 6 weeks inFigure 11. Radiographs at age 3 days showed all bonyelements to be present but the long bones of the limbswere short and gracile (Fig. 12). In addition, there weredislocations of the radial heads and bowing the distalradii. The hypoplasia of the ulnae and radii was not asmarked as in his sister. Severe platyspondyly was pre-sent in all vertebrae, and there was internal decreasein the interpedicular distances in the lower lumbarspine. The pelvis was hypoplastic with mild irregulari-

Fig. 8. Radiograph of lateral spine of patient 2 at age 3 weeks. Notewafer-thin and poorly calcified vertebral bodies.

Fig. 7. Radiograph of patient 2 at age 3 weeks. Note elongated clavicles,poorly calcified vertebral bodies, widened sacrosciatic notch, and tridentconfiguration of the acetabulum.

New Bone Dysplasia With CNS Degeneration 67

ties of the ileac crests, widened sacrosciatic notches,and trident configuration of the acetabula with signifi-cant hypoplasia of the acetabular roofs (Fig. 12). Someof these findings are also seen in Figure 13 when thepatient was 2 months old. The metaphyses throughoutwere normal in appearance. A CT scan of the head atage 9 days was interpreted as normal. Repeat head CTscans at ages 2 and 3 months indicated progressiveventricular enlargement and brain atrophy (Fig. 14).These changes corresponded to his progressive neuro-logic decline.

Shortly after birth, the patient was transferred tothe Neonatal Intensive Care Unit of Riley Hospital forChildren. Because of persistent mild respiratory dis-tress, he was treated with supplemental oxygen by na-sopharyngeal continuous positive airway pressure(CPAP). Over the next 7 days, he was graduallyweaned to room air and was discharged on the twelfthday. At the time of discharge, he only required gavagefeedings. By 5 weeks of age he was being bottle fed, andwas having no major problems. In particular, he hadhad no known apneic spells. Developmentally, hewould respond to people, smile, and fix and follow withhis eyes. However, since birth, his growth had beenvery poor with weight, length ,and OFC at 5 weeksbeing 2,560 g (<3rd centile), 44.5 cm (<< 3rd centile)and 35 cm (−2 S.D.), respectively. Physical findings atthis time were similar to those in the neonatal periodexcept that he had plagiocephaly and a protruding ab-domen. Chest circumference was 30.5 cm (3rd centile).No scoliosis was noted.

When 2 months old, the patient presented at theemergency room with a fever of 2 days duration. Whilethere he was noted to become cyanotic and to haveseveral apneic spells. Bronchoscopy at this time iden-tified 50–75% tracheomalacia with stenosis of the cri-coid and first tracheal cartilage ring. He was admitted

to Riley Hospital for Children where a tracheostomywas done. Following this procedure, he required CPAPto maintain normal blood oxygen saturations. He wascontinued on CPAP until his death 7 weeks later. Cul-tures for infectious agents were sterile.

During the latter hospitalization he had numerousepisodes of oxygen desaturation and bradycardia.These episodes became more frequent and were moredifficult to correct with bag and mash ventilation. Healso experienced progressive neurologic degenerationwhich temporarily correlated with the degree of atro-phy of his central nervous system seen on CT scan. AnEEG done at age 2 months was abnormal and showedmultifocal, sharp transient spikes over the occipital re-gions and to a lesser extent over the frontocentral andtemporal areas. Serum very long chain fatty acids andplasmalogen levels were normal. The karyotype wasalso normal (46,XY).

Because of his deteriorating neurologic status andthe increased difficulty in treating his episodes of de-saturation, the patient was allowed to die at 3 1/2months. At autopsy the heart was enlarged with biven-tricular hypertrophy, right atrial dilatation, and a pat-ent and fenestrated foramen ovale. Tracheomalaciawas confirmed. There also was bilateral pulmonary hy-poplasia with thickened interstitium, focal hemor-rhage, atelectasis, hyaline membrane, and emphyse-matous changes. In addition, bilateral inguinal herniasand a Meckel’s diverticulum were found. On histologicexamination of the cartilage, there was diminished os-sification of the vertebrae, and in general, disorganiza-

Fig. 9. Head MRI of patient 2 at age 17 days indicates normal brain butnarrowing of the caliber of the spinal cord and the cervical medullaryjunction.

Fig. 10. Head CT scan of Patient 2 at age 3 months. Note marked brainatrophy and ventriculomegaly.

68 Khosravi et al.

tion of the cartilage. Analysis of collagen type II alsoshowed no apparent abnormality. The brain was smalland only weighed 280 g (the brain weight of a 32-weekfetus). There were generalized and diffuse atrophy, andencephalomyelopathy of the brain and the spinal cord.The leptomeninges of the cerebral falx were underde-veloped. The vermis was displaced upwardly, and thetentorial aperture was enlarged. The lateral and thirdventricles, and the aqueduct of Sylvius were also en-larged. The cerebral cortex and the corpus callosumwere thin. On histologic examination, there were dif-fuse and severe neuronal loss, gliosis, and generalizedloss of myelin.

DISCUSSION

We present 3 sibs with a distinct bone dysplasia thatis associated with apparent progressive CNS degenera-tion. Each affected sib followed a similar course pre-senting at birth with shortened limbs, and then eachexperienced poor growth, seizures and progressiveCNS degeneration. Each eventually died during in-fancy of respiratory failure secondary to their CNS de-terioration. The radiographic, physical, and autopsyfindings were similar in each case. The histologicchanges in the cartilage of the last 2 infants also were

similar. Brain atrophy which was present in all 3 pa-tients also was associated with enlargement of the ven-tricles. These changes apparently were postnatal onessince an MRI at age 17 days in case 2 and a CT scan atage 9 days in case 3 were normal. No abnormal bio-chemical findings relevant to the cause of the degen-eration were detected in any of the affected infants.

The major condition considered in the differential ofthe disorder presented in this paper is Dyggve-Melchior-Clausen (DMC) syndrome [Schorr et al.,1977; Beighton, 1990].

DMC syndrome is a rare autosomal recessive disor-der characterized by short trunk, rhizomelic shortness,platyspondyly, unusual changes of crista iliacae, andmental deficiency [Dyggve et al., 1977; Spranger et al.,1975, 1976]. Coarse face, prominence of the jaw, andrelative microcephaly are frequent findings in theDMC syndrome [Beighton, 1990]. Increased pipecolicacid has been observed in a number of patients withDMC syndrome [Roesel et al., 1991]. Radiologic changesinclude platyspondyly with notched vertebral body endplate, short long bones with irregular metaphyseal bor-ders, a lace-like appearance of the iliac crest, and hy-poplastic iliac wings [Dyggve et al., 1977; Spranger et

Fig. 12. Radiograph of pelvis and lower limbs of Patient 3 at age 3 days.One can observe the hypoplastic pelvis, widened sacrosciatic notch, tridentconfiguration of the acetabula, hypoplastic acetabular roof, and shortenedand gracile long bones.

Fig. 11. Frontal view of Patient 3 at age 6 weeks. Observe sparse eye-brows and lashes, short nose, depressed nasal bridge, long philtrum, shortneck, and shortened upper and lower limbs.

New Bone Dysplasia With CNS Degeneration 69

al., 1975]. Horton and Scott [1982] studied cartilagefrom iliac crest of a patient with DMC syndrome andreported that chondrocytes in this region were vacu-olated. Many chondrocytes also contained cytoplasmicinclusions. Degenerating clusters of chondrocytes werealso observed.

The ulnar hypoplasia and platyspondyly seen in ourpatients are more severe than that seen in DMC syn-drome. Although the histologic findings of the cartilageof our patients are similar to those seen in DMC syn-drome, our patient’s clinical courses are not typical forthis latter syndrome. The progressive neurologic de-generation present in our patients has not been re-ported in any patient with the DMC syndrome. Fur-thermore, literature and database searches uncoveredonly 1 case of DMC syndrome presenting in infancy, a5-month-old girl reported by Spranger et al. [1975].Clinical findings in this patient were microcephaly,scoliosis and developmental delay. She had some radio-graphic similarity to our cases, particularly the markedplatyspondyly. However, the overall clinical pattern isquite distinct between the patient reported bySpranger et al. [1975] and those reported in this paper.The patient of Spranger et al. [1975] also did not ap-pear to have progressive neurologic deterioration.

Since there are some clinical and radiographic simi-larities, and very similar histopathologic findings inthe cases described here and in the DMC syndrome, itis possible that the cases we describe have 2 separateand nonlinked inherited syndromes, one being DMC

syndrome and the other being a CNS degenerative dis-order. Based on probability alone, this prospect is un-likely, however. The calculated risk of 2 autosomal re-cessive disorders each being present in 3 of 4 sibs isapproximately 9/16,384 (0.000549). Another possibilitywould be a contiguous gene deletion syndrome where amicrodeletion is present with loss of both the gene forDM and a closely linked one leading to the CNS dete-rioration. Some support for this contention comes fromthe fact that families with DMC syndrome have asso-ciated mental retardation while others do not[Spranger et al., 1976]. However, none of the affectedindividuals with mental deficiency and DMC syndromehas had progressive neurodegenerative problems. Athird possibility would be a more severe expression ofthe DMC syndrome; one that previously has not beenreported.

The pathologic assessment of the brains of the latter2 affected infants reported could not absolutely distin-guish between a degenerative process and severe hyp-oxic damage. All 3 children had apneic episodes thatcould have led to brain hypoxia and damage to thebrain, but our observational impression was that theirapnea and respiratory compromise were never of thedegree to be responsible for their CNS findings. In thesecond and third cases, and particularly with the thirdcase, apneic monitoring and ventilation were carefullycontrolled during their last few months of life. In spiteof adequate respiratory support, progressive CNS de-terioration continued and severe brain atrophy devel-oped that ultimately led to the death of these infants.We contend that these individuals had a progressiveneurodegenerative disorder associated with a bone dys-plasia, and do not have atrophy secondary to braindamage. The condition reported here is most likely anautosomal recessive trait.

Fig. 14. A head CT scan of Patient 3 at age 2 months. Note ventricularenlargement and brain atrophy.

Fig. 13. Radiograph of Patient 3 at age 2 months. Note tracheostomy,flat vertebral bodies. Pubic bones are hypoplastic, the iliac crest is slightlyirregular with widened sacrosciatic notch and the acetabulum has a tridentconfiguration.

70 Khosravi et al.

ACKNOWLEDGMENTS

We thank Dorothy Quinlan for her secretarial effortsand to Dr. Mary Edwards-Brown for assistance withinterpretation of brain imagining studies. This studywas partially funded by an NIH Program Project grantHD-22657-10.

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Roesel RA, Carroll JE, Rizzo WB, van der Zalm T, Hahn DA (1991): Dyg-gve-Melchior-Clausen syndrome with increased pipecolic acid inplasma and urine. J Inher Metab Dis 14:876–880.

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