J3Med Genet 1998;35:31-36

Kenny-Caffey syndrome is part of the CATCH 22haploinsufficiency cluster

M A Sabry, M Zaki, S J Abul Hassan, D G Ramadan, M A Abdel Rasool, S A Al Awadi,Q Al Saleh

AbstractWe report four sibs with Kenny-Caffeysyndrome in a consanguineous Bedouinfamily. The first two died in the neonatalperiod while the remaining affectedbrother and sister had all the characteris-tic clinical, biochemical, and radiologicalabnormalities of the syndrome. Theseincluded severe pre- and postnatal growthretardation, cortical thickening of thetubular bones with medullary stenosis,eye abnormalities, facial dysmorphism,hypocalcaemia, and low levels of para-thyroid hormone. The children alsoshowed intracranial calcification, im-paired neutrophil phagocytosis, increasedproportion of B lymphocytes, reducedCD4 and CD8 subpopulations of T lym-phocytes, and inhibited transformation inresponse to Candida antigen. Fluores-cence in situ hybridisation (FISH) wasapplied to blood lymphocyte metaphasespreads from these two Bedouin sibs andtheir parents using probe D22S75(Oncor), specific for the DiGeorge criticalregion on chromosome 22ql1.2. The pres-ence of 22q11.2 haploinsufficiency was

identified in the affected sibs, which was

transmitted from the phenotypically nor-

mal mother. The present report widensthe spectrum ofCATCH 22 microdeletionto accommodate Kenny-Caffey syndrome.(JMed Genet 1998;35:31-36)

Kuwait MedicalGenetics Centre,KuwaitM A SabryS J Abul HassanM A Abdel RasoolS A Al Awadi

PaediatricDepartnent,Farwaniya Hospital,KuwaitM ZakiQ Al Saleh

PaediatricDepartment, SabahHospital, KuwaitD G Ramadan

Correspondence to:Dr Sabry, 4 Channel Close,Rhoose, Vale of GlamorganB62 3EH, UK.

Received 7 March 1997Revised version accepted forpublication 21 July 1997

Keywords: Kenny-Caffey syndrome; CATCH 22;22ql 1.2 haploinsufficiency cluster

The acronym CATCH 22 describes a group ofphenotypically related syndromes, the proto-type ofwhich is the DiGeorge syndrome (MIM188400'), in which a hemizygous microdele-tion has been identified in the juxtacentromericregion (22ql 1.2).2 DiGeorge syndrome is a

developmental field defect of the third andfourth pharyngeal pouches with hypoplasia/aplasia of the thymus and parathyroid glands,congenital hypoparathyroidism, hypocalcae-mia, facial dysmorphism, and cardiac malfor-mation. The velocardiofacial syndrome (MIM192430) is another member of the CATCH 22cluster,3 characterised by the presence of a dis-tinct facies with microphthalmia, strabismus, aprominent nose, a square nasal tip, notchedalae nasi, cleft palate with nasal speech, micro-gnathia, and some cardiac abnormalities, suchas VSD, pulmonary stenosis, double outletright ventricle, and tetralogy of Fallot. Thevelocardiofacial syndrome has been associated

with schizophrenia in some cases.4 Othermembers of the CATCH 22 group include theconotruncal anomaly-face syndrome (MIM217095),5 which comprises a variety of cardiacoutflow tract defects, the Caylar cardiofacialsyndrome with unilateral facial palsy owing tohypoplasia of the depressor anguli oris muscleassociated with congenital heart disease,6 andthe Opitz BBBG syndrome (MIM 145410)with its distinctive oesophageal abnormalities,dysphagia, hypertelorism, and hypospadias.Kenny-Caffey syndrome (MIM 127000,

244460) is another rare disorder of whichapproximately 26 cases have been published. Itis characterised by severe pre- and postnatalgrowth retardation, small, slender long boneswith medullary stenosis, poorly ossified skullbones, delayed closure of the anterior fonta-nelle, and early onset episodic tetany. Impor-tant eye signs in Kenny-Caffey syndromeinclude microphthalmia, corneal opacity,myopia/hyperopia, optic atrophy, macularclouding, papilloedema/pseudopapilloedema,calcium deposition in the cornea and retina,and tortuous retinal vessels. Other traits withvariable presentation in the syndrome arehypoplasic nails and neonatal liver disease.Laboratory defects in Kenny-Caffey syndromeinclude the presence of low serum calcium andmagnesium, high serum phosphorus, neonatalhypoparathyroidism, sometimes with anaemia,eosinophilia, and persistent neutropenia. Theimmunological defect in Kenny-Caffey syn-drome is not consistent with DiGeorge syn-drome and is characterised by the presence of aspecific T cell abnormality in terms ofincreased suppressor fraction CD8 with a con-sequent low helper/suppressor ratio, in addi-tion to reduced T cell response to mitogens.7So far, there is no consensus on the mode of

inheritance of Kenny-Caffey syndrome. Somecases have been described in which sporadic/autosomal dominant or recessive patterns weresuggested.7-" Based on our clinical experiencewith Kenny-Caffey syndrome, coupled withreviewing medical publications on the disease,we noted its phenotypic overlap with DiGeorgesyndrome in which hemizygous 22ql 1.2microdeletion has been identified in mostpatients.2 12 This has prompted us to explorethe possibility that, like members of theCATCH 22 family, Kenny-Caffey syndromemight be associated with a deletion within22ql 1.2. This report describes, for the firsttime, the identification of maternally inherited22ql 1.2 haploinsuffiency in sibs with Kenny-Caffey syndrome. The implications of thisfinding are critically discussed. An abstract of

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Figure 1 Case I showing characteristicfacialfeatureswith deep set, small eyes, low set ears, micrognathia, andirregular, carious teeth. (All photographs reproduced withpermission.)

this work has been communicated to the 29thAnnual Meeting of the European Society ofHuman Genetics.'3

Case reportsCASE 1

This girl was born at term in January 1988 tofirst cousin, healthy, Bedouin parents. Birthweight was 2250 g (<-2 SD). The parents hadfive healthy daughters, two healthy sons, anaffected son (case 2), two affected daughterswho had died (cases 3 and 4), and a stillbornboy. Case 1 was ascertained at the age of 11days because of repeated convulsions with lowserum levels of parathyroid hormone (1.1pmol/l, reference range 1.3-7.6), calcium (1.57mmol/l, reference range 2.2-2.62), and magne-sium (0.45 mmol/l, reference range 0.74-0.99),while serum phosphate was high (4.2 mmol/l,reference range 0.81-1.58) and serum alkalinephosphatase was 203 U/l (reference range50-136). Chest x ray showed a normal thymicshadow. She was given vitamin D and calciumsupplementation with subsequent correction ofher biochemical abnormalities and temporarycessation of the hypocalcaemic seizures whichrecurred at 8 months, at which time her growthparameters were low for her age (weight 5700 g(<-3 SD) and length 57 cm (-5 SD)). Theanterior fontanelle was 1.5 x 2 cm. She wasfound to have frontal bossing, microphthalmia,micrognathia (fig 1), short extremities, andsmall hands and feet. The cardiovascularsystem did not show any abnormality and shehad good head control, but was unable to siteven with support. Investigations at the age of 8months showed that serum calcium was 1.58mmol/l, phosphorus 2.98 mmol/l, magnesium

Figure 2 X ray of case 1 showing cortical thickening andmedullary stenosis of the long bones of the upper limb.

Figure 3 Non-enhanced CT scan of the head of case 1showing intracranial cakification of the frontal lobes andbasal ganglia.

0.6 mmol/l, and alkaline phosphatase 224 U/l.The mother had normal serum levels ofcalcium, phosphorus, magnesium, and alkalinephosphatase. Skeletal survey of the girl showedmedullary stenosis of the tubular bones withcortical thickening (fig 2) and absence ofdiploetic space in the cranial bones. The girlhad several hospital admissions because ofrepeated bacterial infections (pneumonia,

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meningitis, septicaemia, UTI, and chronic oti-tis media with Pseudomonas and S aureus).Immunological testing showed normal serumimmunoglobulin and complement profiles,reduction of both CD4 and CD8 subpopula-tions of T lymphocytes, and increasedproportion of B lymphocytes. Transformationin response to Candida antigen was reducedand there was impaired phagocytosis of Saureus by the patient's neutrophils in autolo-gous serum. At the age of 6 years, she started tohave recurrent corneal ulceration which wascomplicated by corneal opacities. Head CTscan at the age of 7 years showed symmetricalcalcifications of the basal ganglia and frontallobes (fig 3). She continued to grow poorly sothat at 8 years her weight was 8.7 kg, height 87cm, and head circumference (OFC) 42 cm,while her psychomotor development was se-verely retarded. By that time, her teeth weremarkedly decayed and maloccluded. Up to thepresent time, she is still dependent on 1-alphavitamin D, calcium, and magnesium supple-mentation.

Conventional cytogenetic techniques withhigh resolution banding failed to detect anyabnormality in the chromosome constitution ofthe two Bedouin sibs (cases 1 and 2) or in theirparents. Fluorescence in situ hybridisation(FISH) was then applied to blood lymphocytemetaphase spreads from the affected cases,their parents, and from normal control sam-ples. Probe D22S75 (Oncor), specific to theDiGeorge critical region (DGCR) on chromo-some 22ql 1.2, was used along with chromo-some 22q13.3 control probe D22S39 (Oncor),according to the method described by themanufacturer. From each person investigated,20 metaphases were examined. A signal of thecontrol probe was detected on each of thechromosome 22 pair in metaphase spreads ofall persons investigated. DGCR specific probestained the two copies of chromosome 22 ofnormal control samples and of the father of theindex cases. The same probe detected a signalon only one of the chromosome 22 pair fromthe affected subjects and their mother, thusindicating the presence of a maternally inher-ited 22ql 1.2 hemizygous microdeletion in thesibs with Kenny-Caffey syndrome (fig 4). Themother was phenotypically normal, both clini-cally and biochemically.

CASE 2This boy was born at term in July 1995 byLSCS because of fetal distress. Apgar scoreswere 4 and 8 at five and 10 minutesrespectively. Birth weight was 2500 g, length 43cm, and OFC 32 cm. He was found to havebilateral microphthalmia and corneal opacities(fig 5). He was kept in an incubator because ofcyanosis and respiratory distress because ofmeconium aspiration. Initial biochemical in-vestigations were normal, including serum cal-

Figure 4 Fluorescence in situ hybridisation (FISH) ofperipheral blood lymphocytemetaphase spreads from the two sibs with Kenny-Caffey syndrome (cases 1 and 2) and theirparents. N denotes the non-deleted chromosome 22. D or del 22 denote chromosome 22 with22q11.2 microdeletion. (A), (B), (C), and (D) represent case 1, case 2, the phenotypicallynormal mother with the microdeletion, and the unaffectedfather, respectively.

cium (2.2 mmolIl) and phosphorus (1.82mmol/l). At the age of 4 days, however, routineblood testing showed a serum calcium of 1.7mmol/l, albumin 28 g/l, phosphorus 1.62mmol/l, magnesium 0.58 mmol/l, and alkalinephosphatase 348 U/1. These abnormalities

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were reversed initially by the adminstration ofintravenous calcium and magnesium and laterby calcium and vitamin D supplementationand the baby was discharged on day 15 postna-tally. Two months later, he was readmitted withhypocalcaemic seizures and laboratory investi-gations again showed low serum calcium (1.32mmol/l), magnesium (0.56 mmol/l), and para-thyroid hormone (0.9 pmol/l), a high serumphosphorus (3.86 mmol/l), while alkalinephosphatase level was 245 U/1. After correctionof these biochemical abnormalities withintravenous calcium and magnesium, oraltherapy with calcium, magnesium, and vitaminD (1-alpha drops) was instituted. Over the pastone and half years, he has been repeatedlyadmitted with recurrent infections (pneumo-nia, gastroenteritis, UTI, and otitis media).Immunological investigations showed similarabnormalities to those detected in his sister(case 1). Head CT scan at the age of 10 monthsdid not show any intracranial calcifications.Skeletal survey showed medullary stenosis ofthe long tubular bones (fig 6). He was last seenat the age of 18 months when his weight was3800 g, length 57 cm, and OFC 40 cm, all wellbelow the 3rd centile for age. There wasmarked psychomotor retardation with poorhand function and an inability to say anymeaningful words or sit unaided. In addition,he had delayed dental eruption. Since then, hisblood chemistry is being maintained on theprevious therapy (see case 1). Like his sister(case 1), conventional cytogenetic techniquesand high resolution banding did not detect anychromosomal abnormality and identified anormal male constitution (46,XY), while FISHanalysis identified haploinsuffiency at DGCR(22ql 1.2), as mentioned above (fig 4).

CASE 3

Case 3 was a female born at 38 weeks' gestationin November 1984 with a birth weight of 2210g, length of 42 cm, and OFC of 30.7 cm. Shewas incubated because of being small forgestational age and having some dysmorphicfeatures and right corneal opacity. On day 6postnatally, she developed twitching of thefacial muscles followed by apnoea and cyanosiswith fisting. Investigations showed a calciumlevel of 4.6 mg, phosphorus 12.9 mg, andmagnesium 1.3 mg, alkaline phosphatase 213U/l and parathyroid hormone <1.5 mmol/l.Other investigations, including complete bloodcount, blood cultures, CSF analysis, TORCH,and VDRL, were normal/negative. Chest x raywas normal. Treatment consisted of antibiot-ics, calcium gluconate, magnesium sulphate,and vitamin D. She died at 55 days following anapnoeic attack.

CASE 4

Case 4 was a female born at term in February1986 with a birth weight of 2500 g. She wasincubated because of respiratory distress andwas noted to have some abnormal facialfeatures with microcephaly, microphthalmia,bilateral central corneal opacities, and bilateralanterior polar cataract. Chest x ray showedpulmonary infiltration of the right middle zone

..4s

Figure 5 Photograph of case 2 showing the characteristicfacialfeatures: small, deep set eyes, squint, corneal opacities,low set ears, and micrognathia.

Figure 6 Skeletal survey of case 2 showing medullarystenosis of the tubular bones of the lower limbs.

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and appropriate care and antibiotic therapywere administered. At the age of 8 days shedeveloped generalised convulsions. At thattime, investigations showed haemoglobin of1 1.3 g/dl, totalWBC of20 x 10/1 (polymorpho-nuclear cells 66%, lymphocytes 32%), andplatelet count of 184 x 10/1. Blood culture grewcoagulase negative Staphylococcus. Lumbarpuncture was refused by the parents. Serumcalcium was 1.82 mmol/l, phosphorus 1.54mmol/l, magnesium 0.59 mmol/l, and alkalinephosphatase 213 U/1. Parathormone level wasnot investigated. She was given intravenouscalcium and magnesium with normalisation ofthe abnormal biochemical values. Her condi-tion progressively worsened with the develop-ment of recurrent apnoeic episodes and shedied at the age of 18 days.

DiscussionWe report here a Bedouin family in which foursibs fulfilled the criteria for the diagnosis ofKenny-Caffey syndrome. The most consistentdocumented findings in Kenny-Caffey syn-drome include characteristic radiologicalchanges with cortical thickening and medullarystenosis of the long bones (in 96.2% ofpatients), growth retardation (92.3%), normalintelligence (88%), hypocalcaemia/tetany(85%), ocular anomalies (70.8%), and lowparathyroid hormone (58.3%), in addition tosome dysmorphic facial features and smallhands and feet.'4 The diagnosis of Kenny-Caffey syndrome in our Bedouin children isunequivocal, since they showed most of theabove mentioned traits. Some other featureswere identified in our patients that have notbeen reported as a prominent part of theKenny-Caffey phenotype from other parts ofthe world. These features included markedIUGR, severly delayed psychomotor develop-ment, and microcephaly. Such traits arecompatible with recent reports of otherBedouin sibships affected with Kenny-Caffeysyndrome." Apparently, the disease profile inthe Middle East differs to some extent from theKenny-Caffey phenotype described in otherparts ofthe world, which is characterised by thepresence of normal intelligence, late closure ofthe anterior fontanelle with macrocephaly, andposmatal rather than prenatal growth retarda-tion (with adult height ranging between 121and 149 cm).'5

In cases 1 and 2 ofthe present report, growthretardation was so severe that their growthparameters were permanently far below the 3rdcentile for their age. Impaired growth hormonelevel does not seem to play any role in thepathogenesis of the disease since it was normalin our cases as well as in some other reportedcases in which attempts with growth hormonetherapy were unsuccessful.'5 16 Intracranial cal-cification has been previously reported onlyonce in a postmortem examination of a casewith Kenny-Caffey syndrome.'7 It was alsodetected in case 1 of the present report andcould be one factor responsible for the delayedpsychomotor development observed in thiscase. Intracranial calcification in patients with

Kenny-Caffey syndrome may be age relatedand this could be the reason why it has not yetbeen detected in the younger affected brother(case 2).

In our Bedouin patients, we identified amaternally inherited hemizygous microdele-tion in the juxtacentromeric region of the longarm of chromosome 22 (22ql 1.2) that charac-terises the CATCH 22 cluster of diseases.Thus, this report includes Kenny-Caffey syn-drome as a new member of the rapidly increas-ing CATCH 22 family and provides a molecu-lar marker for its accurate diagnosis. To thateffect, the parental consanguinity in ourBedouin family seems to be coincidental anddoes not give additional support to theexistence of an autosomal recessive form ofKenny-Caffey syndrome. However, this reportdoes not totally exclude the presence of"molecular" heterogeneity of Kenny-Caffeysyndrome, analogous to other members of theCATCH 22 family for which a second haploin-suffiency locus on the short arm of chromo-some 10 has been suggested.'8The report also widens the phenotypic spec-

trum ofCATCH 22 to include some new traitsthat characterise Kenny-Caffey syndrome, forexample, the severe pre/postnatal growth retar-dation, the cortical thickening/medullary ste-nosis of the tubular long bones, and the neweye signs described in the introduction of thisreport. This in turn would give more insightinto the corresponding developmental proc-esses and the functional prospects of therecently identified genes at the site of theCATCH 22 microdeletion, particularly thepotential candidates for transcriptionregulation,'9 chromatin assembly,20 embryonicpatterning," 2 mitochondrial transport,23 andadhesion.24

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20 Lorain S, Demkzuk S, Lamour V, et al. Structuralorganisation of the WD repeat protein-encoding geneHIRA in the DiGeorge syndrome critical region of humanchromosome 22. Genome Res 1996;6:43-50.

21 Pizzuti A, Novelli G, Mari A, et al. Human homologuesequences to the Drosophila dishevelled segment polaritygene are deleted in DiGeorge syndrome. Am Hum Genet1996;58:722-9.

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