J7 Med Genet 1994;31:121-125

Microcephaly and congenital nephroticsyndrome owing to diffuse mesangial sclerosis:an autosomal recessive syndrome

Department ofPaediatrics and theKipper Institute ofPaediatricImmunology,Beilinson MedicalCentre, Petah Tiqva49100, IsraelB Z GartyPaediatric NephrologyUnit, BeilinsonMedical Centre, PetahTiqva, and SacklerFaculty of Medicine,Tel Aviv University,IsraelB EisensteinPathologyDepartment,Beilinson MedicalCentre, Petah Tiqva,and Sackler Faculty ofMedicine, Tel AvivUniversity, IsraelJ SandbankThe Genetics Clinic,Mount Sinai MedicalCenter, New York,NY, USAS KaffeDepartment ofPaediatrics, SorokaMedical Centre, BeerSheva, IsraelR DaganNeurologyDepartment,Beilinson MedicalCentre, Petah Tiqva,and Sackler Faculty ofMedicine, Tel AvivUniversity, Israel.N Gadoth

Correspondence toDr Garty.Received 9 February 1993Revised version accepted forpublication 24 August 1993

Ben Zion Garty, Bella Eisenstein, Judith Sandbank, Sara Kaffe, Ron Dagan,Nathan Gadoth

AbstractThree sibs born to consanguineous par-ents had congenital nephrotic syndrome,microcephaly, and psychomotor retard-ation. Pathology of the kidneys showeddiffuse mesangial sclerosis with depositsof IgG and C3 in the mesangium andglomerular basement membranes. Allthree children died before the age of 3years. Of 19 published cases of childrenwith the association of congenital neph-rotic syndrome and microcephaly, onlyfour had histological evidence of diffusemesangial sclerosis, and two of their sibsprobably had the same disease. The asso-

ciation of nephrotic syndrome owing tocongenital diffuse mesangial sclerosis,microcephaly, and mental retardationappears to be a distinct syndrome with anautosomal recessive mode of inheritance.

Nephrotic syndrome in the first year of life(congenital nephrotic syndrome) is rare. In-fantile microcystic disease, or the Finnish typenephrotic syndrome, is the best documentedform of the syndrome.4 Other known causes ofcongenital nephrotic syndrome are intrauter-ine infection,56 renal vein thrombosis,7 andmercury intoxication.8 Minimal change neph-rotic syndrome, congenital focal glomerularsclerosis, membranous glomerulopathy, or dif-fuse mesangial sclerosis are uncommon causes

of nephrotic syndrome in the first year of life."'The association of congenital nephrotic syn-

drome, microcephaly, and mental retardationhas been reported in 19 children,12-2' but onlysix of them had diffuse mesangial sclerosis(table).'121 We report a family with three mic-rocephalic children who had severe psychomo-tor retardation and congenital nephrotic syn-drome owing to diffuse mesangial sclerosis.

(_J Med Genet 1994;31:121-125)

Congenital microcephaly is associated with a

variety of pathological conditions, includingchromosomal aberrations, metabolic diseases,intrauterine infections, postradiation injury,and chronic hypoxaemia.' In its isolated form,it is usually inherited in an autosomal recessivemode2 and is accompanied by severe mentalretardation. Occasionally it is inherited in an

autosomal dominant mode, and in thesepatients the retardation is usually milder.`3

Case reportsThe family was of Jewish North African ori-gin. The pedigree is shown in fig 1. There were

consanguineous marriages in generations IIIand IV-V. The father of the proband was themother's uncle. Except for the proband andtwo of his sibs, there were no other familymembers with kidney disease or psychomotorretardation. The other five sibs, as well as theparents, were healthy and did not have micro-cephaly. The mother of the proband did notsmoke and had not taken medication or alcohol

Clinical and pathological findings in the patients with congenital nephrotic syndrome owing to diffuse mesangial sclerosis and microcephaly

Case Sex Micro- Onset of Kidney Mental Neurological Dysmorphic Age at Notes Refcephaly nephr syn histology retardation symptoms features death

1 F + 1 d Mesangial sclerosis + Seizures No 3 mth 162 M + 6 d Diffuse mesangial ? Decreased vision & Wide set eyes;

sclerosis hearing small nose 2 mth 193 F + 6 d Mesangial sclerosis Hypertonic arms; Floppy ears; contractures 2 mth 20

seizures of hands & feet4 M + 12 d - NM NM Floppy ears; I mth Sib of 20

hypertelorism case 35 M + 14 mth Mesangial sclerosis Severe Seizures; hypertonic limbs; Micrognathia; 18 mth 21

poor head control; no large earsvisual fixation

6 F + 9 mth - Severe Hypertonic limbs; seizures; Large ears; 3 y Sib of 21poor vision & hearing small midface case 5

7 M + 1 mth Diffuse messangial Severe Hypertonic limbs; poor Large, low set, floppy 2 y Consan- Presentsclerosis. IgG and head control; strabismus; ears; sparse, thin hair; guinity reportC3 deposit in the poor vision & hearing micrognathia; bilateralmesangium undescended testes

8 F + 1 mth Identical to case 7 Severe Identical Large, low set, floppy 15 mth Sib of Presentears; sparse hair cases 7 & 9 report

9 M + 1 y - Severe Hypertonic limbs ? 3 y Presentreport

NM = not mentioned.

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III

IV

Iv

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Figure 1 Family pedigree.

during the pregnancies. Data regarding pla-cental weight of the different pregnancies andalphafetoprotein measurements are not avail-able.

CASE 1 (VI.8)The boy was the term product of a normalpregnancy and delivery. Birth was 4400 g andmarked microcephaly was noted.During the first months of life, generalised

oedema, recurrent vomiting, and psychomotorretardation were seen. On admission, at the ageof 11 months, the patient had puffy eyes andmild pitting oedema of the ankles and sacrum.

Blood pressure was 100/60 mmHg, pulse rate110/minute, and respiratory rate 24/minute.Weight was 8000 g (3rd centile for his age),length 74 cm (60th centile for his age), andhead circumference 40 cm (- 5 SD below themean for his age). The nose was small and theears were large and low set, with unusuallysoft auricles. Strabismus, high arched palate,micrognathia, and sparse, thin hair were alsopresent. Examination of the heart and lungsshowed no abnormalities. There was no viscero-megaly and the kidneys were not palpable. Thescrotum was underdeveloped with bilateralundescended testes. The penis was normal.There was bilateral overlapping of the first toeby the second.

Neurological evaluation disclosed poor headcontrol, inability to sit up or turn, and absenceof interest in his surroundings. The anteriorfontanelle was small and barely palpable. Thecranial nerves were unremarkable. Motor ex-

amination showed muscle wasting without fas-ciculation and absence of purposeful move-

ments. Strength was decreased mainly in the

proximal muscles, with a tendency to hyperto-nicity and scissoring of both legs. The fistswere constantly clenched. Pain sensation wasgrossly intact and deep tendon reflexes werehyperactive with flexor plantar responses. Thepatient neither responded to noise nor fol-lowed objects with his eyes for more than a fewseconds. Constant head rolling was presentand he seldom smiled. Fundoscopic examina-tion was normal.

Laboratory data showed haemoglobin11-3 g/dl, white blood count 7 x 109 cells/l(45% neutrophils, 40% lymphocytes, 15%monocytes), platelets 460 x 109/l, blood ureanitrogen 3 9 mmol/l, and creatinine 35-4 imol/1. Total serum protein measured 30 g/l, withalbumin 19 g/l; C3 component of the comple-ment was 1.3 g/l, C4 0-3 g/l, CH50 70%. Cho-lesterol was 0-65 mmol/l, triglycerides0 75 mmol/l, and total lipids 4-6 mmol/l. IgGwas 2-3 g/l (normal for age: 7-2 ± 2 7 g/l), IgA0-6 g/l (normal: 0 7 ± 0 3 g/l), IgM 1-3 g/l (nor-mal: 0 63 + 0 3 g/l). Urine analysis showed 5 to10 erythrocytes in high power field and granu-lar casts. Daily urinary protein excretion was3-8 to 4-8 g (mainly albumin). Creatinine clear-ance was 100 to 105 ml/min/1 73 m2.The following laboratory tests were normal:

serum sodium, potassium, chloride, calcium,phosphorus, magnesium, bilirubin, aspartateaminotransferase (SGOT), lactate dehydroge-nase (LDH), creatinine kinase (CK), uric acid,pH, lactate, pyruvate, T4, serology for rubella,toxoplasma, cytomegalovirus and syphilis,cerebrospinal fluid, electrocardiography, elec-troencephalography, and electromyography.The karyotype was of a normal male. Intra-venous pyelography showed mild enlargementof both kidneys. Skull radiography disclosed asmall cranium; the rest of the skeletal radio-graphic survey was normal. Bone age was 9months. Cerebral CT scan showed a smallposterior fossa with enlargement of the fourthventricle and ambient cisterna compatible withcerebellar hypoplasia. There was also a milddegree of enlargement of the lateral and thirdventricles (fig 2).

Percutaneous kidney biopsy showed hyper-cellularity of mesangial cells, an increase inPAS positive material in the mesangial matrix,and mild thickening of the capillary wall. Oc-casional segments showed obliteration of theirnormal structure. A few immature glomeruliwere noted, as well as microcystic transforma-tion of a few tubuli (fig 3). Electron micro-scopy of the glomeruli showed effacement ofthe epithelial foot processes and dilatation ofthe mesangium owing to hypercellularity andabundance of matrix. Electron dense depositswere present in the subendothelial region ofthe peripheral and axial glomerular basementmembrane and in the mesangium. The laminadensa was irregular and sometimes thinner andsometimes thicker than usual (fig 4). Immu-nofluorescence staining showed massive de-posits of IgG and C3 in the mesangium andglomerular basement membrane. These find-ings suggested the diagnosis of infantile diffusemesangial sclerosis. The patient was dis-charged and was lost to detailed follow up. He

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Microcephaly and congenital nephrotic syndrome owing to diffuse mesangial sclerosis: an autosomal recessive syndrome

Figure 2 Cerebral CT scan showing enlargement of thefourth ventricle and cerebellar hypoplasia.

developed renal failure and died at the age of 2years.

CASE 2 (VI.3)The sister of case 1, born at term after anuneventful pregnancy and delivery, was ex-amined at the age of 12 months. Head circum-ference was 39 5 cm (-5 SD below the meanfor her age). There was poor head control andsevere psychomotor retardation. Deep tendonreflexes were hyperactive and the limbs were

spastic. She could not turn and showed nointerest in her surroundings or in social com-munication. Pitting oedema of the ankles andsacrum was present. She had strabismus,sparse hair, and large, low set, floppy ears, likeher brother.

Laboratory tests showed hypoproteinaemia,hypoalbuminaemia, and hyperlipidaemia(total lipids were 1040 mg/dl). Urine analysisshowed massive proteinuria, microscopichaematuria, and granular casts. Kidney biopsyshowed similar changes to those seen in case 1.She was treated with 2 mg/kg/day of predni-sone but without apparent effect. During thesecond year of life, rapid deterioration in kid-ney function occurred, and serum creatininelevel reached 530 gmol/l. She died at the age of15 months of E coli septicaemia. Necropsycould not be performed.

CASE 3 (VI.1)This patient, the brother of patients 1 and 2,also had a "little head", hypertonia of thelimbs, severe psychomotor retardation,oedema, and proteinuria. His kidney functiondeteriorated gradually and he died before theage of 3 years. The clinical evaluation of thispatient was performed at another hospital andkidney histology was not available.

DiscussionThe characteristic features of congenital neph-rotic syndrome associated with microcephalyare severe mental retardation, rapid deteriora-tion of kidney function, unresponsiveness tomedication, and usually fatal outcome beforethe age of 3 years. Nineteen cases of thisassociation, first described by Galloway andMowat,'2 have been reported.12-2' Additionalfindings include neurological abnormalities,

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Figure 4 Electron microscopy ofglomerular tuft showing subendothelial andparamesangial subendothelial deposits (arrow heads), increase in mesangial matrix(thick arrow), thinning of lamina densa (short thin arrows), and partial effacement offoot processes (long thin arrows).

such as abnormal muscle tone and seizures,and minor dysmorphic features, such as an

unusually shaped head, low set, floppy ears,

micrognathia, and, occasionally, hiatus her-nia.'2-14 Histology of the kidneys was reportedin 12 of the 19 affected patients. However,some were evaluated by light microscopy onlyand in most cases immunofluorescence stain-ing was not mentioned. Some patients under-went renal biopsy and in others tissue was

obtained at necropsy. Thus, the available in-formation on kidney histology is incomplete. Ifwe divide the patients according to the classifi-cations of Habib and Bois" and Kaplan et al,9four had diffuse mesangial sclerosis,'-21 threemicrocystic dysplasia,'2 14 three focal glomeru-losclerosis,'41620 one had mesangial prolifera-tion,21 and one a combination of microcysticdysplasia and focal glomerulosclerosis." De-spite the variability in kidney histology, most

patients had a similar clinical course of declin-ing renal function and early death. Only two

patients reached the age of 5 years.'620 How-ever, it is clear that, based on renal histologyfindings, these are different entities. A similardeteriorating clinical course was also noted inthe patients with the "isolated" form of con-

genital nephrotic syndrome,22 without micro-cephaly.Our patients' kidney histology showed dif-

fuse mesangial sclerosis. Congenital nephroticsyndrome resulting from diffuse mesangialsclerosis has been reported in association withocular abnormalities (nystagmus, cataract, or

microphthalmia),2324 male pseudohermaphro-ditism and Wilms's tumor (Drash syn-

drome),21 or microcephaly.Of special interest in our patients is the

finding of IgG and C3 deposits in the mesan-

gium and of IgG deposits along the basement

membrane. No immune complex depositswere mentioned in the other cases of congen-ital nephrotic syndrome and microcephaly,except for a patient with focal glomeruloscler-osis reported by Roos et al,'6 who showeddeposits of IgM in the basal membrane of thecapillary loops, and the patient with mesangialproliferation, reported by Cooperstone et al,2'who had segmental distribution of fine granu-lar deposits of IgM.

In patients with "isolated" congenital neph-rotic syndrome owing to diffuse mesangialsclerosis (without microcephaly), occasionaldeposits of immune complexes were noted.For example, of three sibs with diffuse mesan-gial sclerosis one had mesangial deposits ofIgG, IgM, C3, and fibrinogen, while the othertwo, although they had a similar kidney dis-ease, had no demonstrable deposits of immunecomplexes.'0 This may have related to thestage of disease or to its differing pathogenesis.No specific metabolic abnormalities were

found in our patients or in those previouslyreported. The neurological abnormalities andthe mental retardation are probably secondaryto the severe microcephaly and the abnormalbrain structure. The mental retardation incases of severe microcephaly is negatively cor-related with brain volume, especially inpatients with autosomal recessive microce-phaly.2 Although brain histology was not avail-able in our cases, brain CT scan suggestedgeneral atrophy, which was more pronouncedin the subependymal zone, and cerebellarhypoplasia. In two previously reportedpatients with congenital nephrotic syndromeowing to diffuse mesangial sclerosis and micro-cephaly, the brain histology showed micro-gyria in the frontal, parietal, and occipitallobes20 and pachygyria with neuronal ecto-pia. 20 The association of congenital kidneydisease and neural migration defect was alsoreported in two other male sibs with glomeru-lar kidney disease causing proteinuria and hy-drocephalus.26 This may suggest a commoninsult during the first weeks of gestation affect-ing both the kidneys and the brain.Four of the 19 previously reported children

with congenital nephrotic syndrome and mic-rocephaly had histological findings of diffusemesangial sclerosis. 1821 Two sibs of thesepatients202' probably had the same kidney dis-ease as well. Thus, two of the previouslyreported patients were sporadic cases, and theother four were pairs of brothers and sistersborn to non-consanguineous parents.202' Thefact that our three patients were sibs (two boysand a girl of a family of eight sibs) and thattheir parents were consanguineous, supportthe assumption of autosomal recessive inherit-ance of this syndrome.

We are indebted to Professor Mina Ben Bassat of the PathologyDepartment for her help and suggestions.

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2 Hecht F, Kelly JV. Little heads: inheritance and earlydetection. J Pediatr 1979;95:731-2.

3 Merlob P, Steier D, Reisner SH. Autosomal dominant

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