American Journal of Medical Genetics 5625-30 (1995)

Cystic Kidney Disease in Hajdu-Cheney Syndrome

Paige Kaplan, Feliciano Ramos, Elaine H. Zackai, Richard D. Bellah, and Bernard S. Kaplan Divisions of Genetics and Nephrology, Department of Pediatrics (P.K., F.R., E.H.Z., B.S.K.) and Department of Radiology (R.D.B.), the Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania

We report on 2 unrelated patients with Hajdu-Cheney acroosteolysis syndrome, who had cystic kidneys with ultrasono- graphic changes similar to those of auto- soma1 dominant polycystic kidney disease. Neither had a family history of Hajdu- Cheney syndrome or polycystic kidneys, nor manifestations of any other syndrome. On the basis of the findings in these 2 patients and a review of published cases, we suggest that cystic kidneys are an important compo- nent of Hajdu-Cheney syndrome. 0 1995 Wiley-Liss, Inc.

KEY WORDS: cystic kidneys, Hajdu-Cheney syndrome, acroosteolysis

INTRODUCTION It has become a convention to restrict the term “poly-

cystic kidney disease” (PKD) to autosomal dominant polycystic kidney disease (ADPKD) and ptosomal re- cessive polycystic kidney disease (ARPKD) [Kaplan et al., 19893. However, polycystic kidneys in infants and children also can be classified into those that are non- syndromal and syndromal (Table I). Syndromal PKD occurs in tuberous sclerosis [Bernstein et al., 1986; Kandt et al., 19921, von Hippel Lindau syndrome [Lamiell et al., 19801, oro-facial-digital syndrome type I [Kennedy et al., 1991; Salinas et al., 19911, and overlap connective tissue disorder (OCTD) [Somlo et al., 19931. PKD has also been reported in 2 cases of Ehlers-Danlos syndrome [Lewitus, 1956; Imahori et al., 19691.

“Adult” PKD has been reported in one patient [Rosenmann et al., 19771, and cystic kidneys have been reported in 4 others with Hajdu-Cheney syndrome, which is inherited as an autosomal dominant trait. The

Received for publication March 15,1994; revision received July 11, 1994.

Address reprint requests to Paige Kaplan, M.B., B.Ch., Division of Genetics, The Children’s Hospital of Philadelphia, University of Pennsylvania, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.

0 1995 Wiley-Liss, Inc.

Hajdu-Cheney acroosteolysis syndrome [Cheney, 1965; Matisonn and Ziady, 1973; Williams, 1977; Herrmann et al., 1973; Gilula et al., 1976; Kawamura et al., 1991; Kemp et al., 1986; Udell et al., 1986; Kaler et al., 1990; Pellegrini and Widdowson, 19911 mainly involves the skeleton. Patients have a characteristic face (hirsute, with ‘proptosis,’ midfacial flattening, long ill-defined philtrum, small mouth, receding chin, and short neck), short stature, osteoporosis in childhood, late-onset bone resorption of the distal phalanges, and progres- sive basilar invagination and central nervous system impairment. The resultant effects tend to overshadow the involvement of other organs such as the kidneys and gastrointestinal tract, which, however, can be a cause of morbidity and death. We report on 2 unrelated patients with Hajdu-Cheney syndrome who had cystic kidneys with ultrasonographic findings similar to those of ADPKD. Neither had findings of any other syn- drome. On the basis of the findings in these 2 patients and a review of published cases, we suggest that cystic kidney disease is an important component of Hajdu- Cheney syndrome.

CLINICAL REPORTS Patient 1

SM (DOB 12-28-1969), a Caucasian boy, was the product of a 36-week gestation. The mother was G4, P3, Al. There was no known parental consanguinity. Both families were Pennsylvania Dutch. Birth weight was 2.8 kg (third centile).

The baby had micrognathia, high-arched cleft palate, low-set ears, ear tags (familial), right-sided cataract, short neck, redundant skin, bilateral simian creases, and hypotonia. By 10 weeks he had feeding problems, vomiting, and failure to thrive. Intestinal malrotation and agenesis of the omentum were detected at surgery. Umbilical and bilateral inguinal herniae and unde- scended testes were repaired. An intravenous pyelo- gram showed “normal function” and malrotated kid- neys with unusual collecting systems. Chromosomes were 46,XY (1970).

At age 15 months, blood pressure was 1701100 torr. A patent ductus arteriosus was ligated at age 2 years. He had a “coarse” facial appearance. He had unex- plained, persistent hypochromic anemia (9.8 gldl) with burr cells. He sat a t 2 years, and walked and talked at 2Y2 years. He had recurrent otitis media, pneumonia,

26 Kaplan et al.

TABLE I. Conditions Associated With Renal Imaging Findings Similar to ADPKD

Chromosome locus Extrarenal manifestations inheritance" and renal tumors

PKDl 161313.3 AD Hepatic cysts, pancreatic cysts, colonic [Eurouean Polvcvstic Kidnev Disease Consortium. 19941 diverticulae. mitral valve urolause. " " PKDi [Peters et al., 19931 PKD [Daoust et al., 19931 PKDl and Overlap Connective Tissue Disorder (OCTD) [Somlo et al., 19931

Tuberosclerosis complex [Kandt et al., 19921

von Hippel-Lindau syndrome [Lamiell et al., 19801

Oro-facial-digital type I [Salinas et al., 1991; Kennedy et al., 19911

Hajdu-Cheney [Rosenmann et al., 19771

4q13-23 AD

?AD

berry aneurysm, inguinal hernia

16p cosegregation AD Aortic root dilatation, aortic and vertebral artery aneurysms with dissection, aortic valve incompetence, pectus, pes planus, joint laxity, arachnodactyly, dolichostenomelia, high-arched palate

Infantile spasms, ash-leaf macules, facial angiofibroma, shagreen patch, periungual fibroma, cortical tubers, subependymal or cortical calcifications, retinal hamartomas, renal carcinoma, angiomyolipoma

Central nervous system and retinal hemangioblastoma, pancreatic, hepatic, and epididymal cysts, pheochromocytoma, angioma, renal carcinoma

Mental retardation, CNS and facial ano- malies, pseudocleft upper lip, polysyndactyly, usually lethal in males

Short stature, abnormal skull, distinctive facies, hoarse voice, progressive skeletal dysplasia, acroosteolysis of terminal phalanges, loss of teeth

16p AD

3P AD onset 4th decade

X-LD

AD

"AD, autosomal dominant; X-LD, X-linked dominant.

and bronchitis. Hearing impairment since early in- fancy necessitated hearing aids. At age 4 years, hyper- tension was treated with hydralazine and then with captopril and aldomet. At age 7 years he began to bruise spontaneously. At age 12 years he had a urinary tract infection.

At age 13 years (Fig. l), weight was 25.5 kg (<third centile), height was 126 cm (<third centile), and occi- pito-frontal circumference (OFC) was 57 cm (>98th centile). He had a bossed forehead, prominent occiput, bitemporal narrowness, prominent jowls, hirsutism with low anterior and posterior hairlines, apparently low-set ears, flat nasal bridge with flared nares, inabil- ity to open his mouth completely, high-arched palate, absent central incisors, and umbilical hernia. He had thick, irregular, stubby fingers, hyperconvex nails, bi- lateral radial dislocation, hypermobility of hands, knees, and toes, genu valga, and scoliosis. BUN was 130, serum creatinine 11, serum calcium 5.8, and serum phosphorus 8.5 mgldl. A renal scan showed bi- lateral decreased function. Ultrasonography showed changes similar to those of ADPKD (Fig. 2). A voiding cystourethrogram showed bilateral reflux and a right bladder diverticulum. Radiologic studies showed re- sorption of distal phalanges (Fig. 31, thin ribs, pointed scapular tips, renal osteodystrophy, loss of cervical lordosis, marked thoraco-lumbar kyphosis, increased vertical height of thoracic vertebral bodies, lower tho- racic spinal osteodystrophy, spondylolisthesis of L5, S1,

and spina bifida occulta. Bone age was 12 years. Chronic peritoneal dialysis was started at age 13 years.

At age 16 years, hydrocephalus developed and a shunt was inserted. A skull X-ray showed diastasis of all sutures, multiple Wormian bones, thickened cal- varia with thickened diploic space, enlarged sella tur- cica, elevated clivus, and platybasia. There were mandibular hypoplasia and increased numbers of max- illary teeth. The frontal sinuses were not apparent. CT of the head was done because he became obtunded. This showed marked basilar invagination (the anterior arch of C1 was at the same level as the suprasellar cistern) and intracerebral hemorrhages. He died, but an au- topsy was not done.

There was no known family history of renal disease, polycystic kidneys, or Hajdu-Cheney syndrome. A ma- ternal great-uncle was reported to be mentally re- tarded with hypertrichosis and coarse appearance.

Patient 2 GB (DOB 11-08-1981), a Caucasian girl, was born af-

ter an uncomplicated gestation. The mother was G3 P2 AO. Weight was 3.18 kg (50th centile), length 50 cm (50th-75th centiles), OFC 35 cm (75th centile). She had an unusual appearance (Fig. 4): flat forehead, bilateral proptosis, wide-spaced eyes, midface hypoplasia, bul- bous nose, prominent upper lip, narrow palate, bifid uvula, micrognathia, and low-set ears. She had single

Cystic Kidney Disease in Hajdu-Cheney Syndrome 27

palmar creases, bilateral clinodactyly, contractures of fingers, mesomelic shortness of arms, broad thumbs and great toes, and bilateral calcaneo-valgus. All the large joints were dislocated. Skull sutures were wide on palpation. Radiologic studies showed normal bone den- sity, a narrow skull base, shallow orbits, dislocated hips, elbows, and right radius, thin bowed “serpentine” fibulae (Fig. 5), broad ulnae, and short metacarpals. Chromosomes were 46,XX. At age 4 moths a gibbus was noted at L4-L5. By age 13 months, she had a mild hear- ing deficit; the stapes were absent and there was an in- complete number of turns in the cochlea. She sat at age 9 months, walked at age 16 months, and spoke words before a year. At age 2 years, radiologic studies (Fig. 6) showed mesomelic shortness of the forearm and dislo- cation of the radial head, but there was no evidence of osteolysis of distal phalanges, nor of osteoporosis. At age 30 months height was 89 cm (25th centile), and OFC was 52.75 cm (>98th centile). At age 4 years height was 95 cm (<third centile), and arm span 85 cm.

At age 4 years she was evaluated for urinary tract infections and dysfunctional voiding. A vesico-urethro-

Fig. 3. Patient 1. Radiograph of the hands and fingers at age 6 years. The arrows indicate diffuse acro-osteolysis of the distal tufts.

gram demonstrated bilateral vesico-ureteral reflux (Fig. 7). Renal function was normal. Renal ultrasono- graphy (Fig. 8) showed bilateral cortical and medullary cysts. At age 11.5 years she complained of low back pain, and radiologic studies showed degenerative changes of the intervertebral spaces, spondylolisthesis of L5-S1, and a compression fracture of L3. She had os- teolysis of the distal phalanges and numerous fractures (ulna, metatarsals) and symmetrical bowing of the fibu- lae. She had a deep, hoarse voice, broad short face (Fig. 9a), bilateral ptosis and proptosis, thick eyebrows with synophrys, long flat philtrum, wide mouth, small man- dible (Fig. 9b), protuberant ears, short neck, mesomelic shortness, especially of the upper limbs, hirsutism, joint laxity, dental problems, and conductive hearing loss. Intelligence was normal. Skull radiographs showed thickening of the bones, prominent occiput, ab- sent frontal sinuses, persistence of all sutures, and Wormian bones. In the cervical spine there was a nar- row C3-C4 space and basilar invagination with the odontoid 5 mm above the basilar line. An upper gas- trointestinal barium study showed intestinal malrota-

28 Kaplan et al.

Fig. 4. Patient 2. Fig. 5. Patient 2. AP view of the lower Fig. 6. Patient 2. AP view of the upper limbs shows svmmetric bowing of both fibu- limbs shows mesomelic shortness of the lae (arrows).

tion. CT with enhancement showed that 2 ossicles of the left ear were malformed and malpositioned.

She was referred for a renal consultation in June 1993 for evaluation of the cystic kidneys. There was no family history of renal failure, polycystic kidneys, hy- pertension or Hajdu-Cheney syndrome. Ultrasono- graphy of parents and sib showed normal kidneys. A paternal aunt and cousin were reported to have Ehlers- Danlos syndrome. The patient had no urinary symp- toms. Blood pressure was 103/71 torr. Urinalysis was normal. BUN was 18 mg/dl, and serum creatinine concentration was 0.7 mg/dl. The serum electrolyte concentrations were normal.

DISCUSSION These 2 patients had typical Hajdu-Cheney syn-

drome and cystic kidneys. Cystic renal disease has been reported in 3 patients with Hajdu-Cheney syndrome, and in 2 with serpentine fibula-polycystic kidney syn- drome [Exner, 1988; Majewski et al., 19931. However, because the manifestations of serpentine fibula-poly- cystic kidney syndrome appear to be the same as those of Hajdu-Cheney, we have included those 2 cases in our analysis. Rosenmann et al. [19771 reported on a boy who died at age 15 years. He had rapidly progressive glomerulonephritis and the typical pathologic findings of “adult polycystic kidneys” at postmortem examina- tion. In an infant who died on the second day of life [Van den Houten et al., 19851, there was no urinary tract ob- struction; histopathologic studies showed multiple, bi- lateral, small, renal cortical cysts without any evidence

- forearm and dislocation of the radial head. There is no evidence of osteolysis of distal phalanges.

of dysplasia. His mother, who also had Hajdu-Cheney syndrome, did not have cysts in her kidneys. “Some- what” large kidneys were noted by intravenous urogra- phy in a newborn infant with a possible abdominal mass [Zahran et al., 19841. This patient also had glan- dular hypospadias, and was hypertensive at age 5 years. Although a diagnosis of renal cystic dysplasia was made by ultrasonography, it is probably inaccurate to call it dysplasia because the kidneys were larger than normal, they had not been examined histologi- cally, and the patient became hypertensive. Using ul- trasonography, Exner [19881 found multiple medullary cysts in the kidneys of a 5-year-old with normal renal function. This was interpreted as a typical polycystic pattern of the parenchyma of both kidneys. Majewski et al. [19931 mentioned that multiple bilateral cysts were detected by ultrasound examination in the kid- neys of their female patient. There was no information on the age at which cysts were first detected, nor on blood pressure or renal function. Vesico-ureteral reflux, with spontaneous resolution, was demonstrated in our patients and in the case reported by Majewski et al. [19931. The patient reported by Rosenmann et al. [19771 and our patient 1 were in chronic renal failure at the time of their death.

We estimate that the prevalence of cystic kidneys in Hajdu-Cheney syndrome is not less than 10%. In con- trast, the incidence of ADPKD is 1 in 3,000 in the gen- eral population. However, there may be underreporting of renal disease in Hajdu-Cheney for several reasons. Affected patients may be asymptomatic at the time of reporting. Our first patient was diagnosed only in the

Cystic Kidney Disease in Hajdu-Cheney Syndrome 29

Fig. 7. Patient 2. A voiding cysto-urethrogram demonstrates bilat- eral reflux.

second decade, and our second patient was diagnosed presymptomatically by ultrasonography. Ultrasonogra- phy was not available in all cases reported in the older literature and, therefore, asymptomatic cystic kidneys might not have been diagnosed. The reasons for diagno- sis in 4 reported cases were glomerulonephritis [Rosen- mann et al., 19771, an abdominal mass [Zahran et al., 19841, an autopsy on a 2-day-old boy [Van den Houten, et al., 19851, and an investigation for syndrome identifi- cation [Exner, 19881. No explanation was offered for the performance of the ultrasound examination in the fifth case [Majewski and Voit, 19931. The cysts can develop prenatally Wan den Houten et al., 19851. The expres-

Fig. 9. a,b: Patient 2.

sion of cystic kidneys is variable, in that not all affected subjects with Hajdu-Cheney have cystic kidneys as ex- emplified by the mother of the 2-day-old boy with renal cysts Wan den Houten et al., 19851. Onset of end-stage renal failure is also variable, but there is insufficient in- formation to make any statements about prognosis.

Our patients had ultrasonographic findings compati- ble with PKD, but we do not have sufficient evidence to state unequivocally that they had ADPKD. They have a form of cystic kidney disease associated with a well- defined syndrome (Hajdu-Cheney). There were no man- ifestations of ARPKD, tuberous sclerosis, or von Hippel Lindau disease. All patients with Hajdu-Cheney &- drome should have renal ultrasonography to anticipate and treat renal failure. The occurrence of cystic kid-

Fig. 8. Patient 2. Cortical and medullary macrocysts are seen in this sonogram of the left kidney (arrows). The right kidney was simi- larly affected.

30 Kaplan et al.

neys, skeletal, and other anomalies may help to eluci- date the cause of the syndrome. A connective tissue disorder [Somlo et al., 19931 could explain many mani- festations of Hajdu-Cheney syndrome.

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