Hereditary renal disease and preauricular pits: Report of a kindred

948

Clinical and laboratory observations

REFERENCES 1. Posen S, Lee C, Vines R, Kilham H, Latham S, Keefe JF: Transient hyperphosphatasemia of infancy: An insufficiently recognized syndrome. Clin Chem 23:292, 1977. 2. Wilson JW: Inherited elevation of alkaline phosphatase activity in the absence of disease. N Engl J Med 301:983, 1979. 3. Kruse K: Inherited isolated hyperphosphatasemia. Acta Paediatr Scand 72:833, 1983. 4. McComb RB, Bowers GN Jr, Posen S: Alkaline phosphatase. New York, 1979, Plenum Press, pp 547-549. 5. Mabry CC, Bautista A, Krik RFH, Dubilier LD, Braunstein H, Koepke JA: Familial hyperphosphatasia with mental retardation, seizures, and neurologic deficits. J PEDIATR 77:74, 1970. 6. Price PA, Parthemore JG, Deftos L J: New biochemical marker of bone metabolism. J Clin Invest 66:878, 1980.

The Journal of Pediatrics June 1985

7. Brown JP, Delmas PD, Malaval L, Edouard C, Chapuy MC, Meunier P J: Serum bone gla-protein: A specific marker for bone formation in postmenopausal osteoporosis. Lancet 1:1091, 1984. 8. Kruse K, Kracht U: Total hydroxyproline: Creatinine ratio in morning fasting urine specimens (OH-p/Cr): A reliable index of bone turnover in children. Monatsschr Kinderheilkd 131:797, 1983. 9. Hausamen TU, Helger R, Rick W, Gross W: Optimal conditions for the determination of serum alkaline phosphatase by a new kinetic method. Clin Chim Acta 15:241, 1967. 10. Yoshida A: Amino acid substitution (histidine to tyrosine) in a glucose-6-phosphate dehydrogenase variant (G6PD Hektoen) associated with over-production. J Mol Biol 52:483, 1970.

Hereditary renal disease and preauricular pits." Report of a kindred Ave M. Lachiewicz, M.D., Richard Sibley, M.D., and Alfred F. Michael, M.D. Minneapolis, Minnesota

RENAL DISEASE and preauricular pits are known to occur in families; however, these have not been associated except in branchio-oto-renal syndrome/ We report a large kindred with both preauricular pits and renal disease.

METHODS This white family of British and Irish descent emigrated to Ohio in the 1800s, then settled in Nebraska. Many relatives still live in Nebraska, but the remainder are scattered throughout the country. The pedigree was obtained from three members who have kept careful records of relatives with preauricular pits and renal disease. A genealogy was also available for reference. The progenitor (I-1) became disabled with renal and pulmonary disease when he was a soldier in the Civil War (Army records were obtained to verify this). Four relatives were evaluated at the University of Minnesota Hospital, eight were evaluated at the Mayo Clinic, and eight were evaluated at other medical centers. Other adults were

From the Departments of Pediatrics, Laboratory Medicine, and Pathology, University of Minnesota Medical School. Submitted for publication July 16, 1984; accepted Oct. 31, 1984. Supported by Grants Al10704, AM25513, and AM26149 from the National Institutes of Health, Viking Children's Fund. Reprint requests: Alfred F. Michael, M.D., Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455.

contacted by letter or telephone and asked about their health and that of their children. Medical records were requested when renal disease was suspected. Death certificates were obtained to confirm the cause of death when no other information was available. Four family members have had renal biopsies or nephrectomies, and these are described. Audiograms were obtained in two members to rule out hearing loss; and karyotyping was performed in one. Chi-square analysis with the Yates modification was used to test the hypothesis that both malformations are genetically related rather than concurrent. Penetrance was

[

BOR

Branchi~176176

syndr~

[

calculated by dividing the number of affected members by all known carriers of the gene. (Figure and Table).

RESULTS Of 130 family members, 12 have preauricular pits and renal disease, 10 have only preauricu!ar pits, and three have only renal disease. Eight developed proteinuria at a young age. Males have more severe renal disease. The nephrectomy specimen from patient V-41 was consistent with simple hypoplasia. Th e kidneys were small, weighing 29 and 39 gin, and there were fewer than 5 reniculi in each. Microscopically, the remnant k~dney

Volume 106 Number 6

nrg

Clinical and laboratory observations

2

+

949

4

fi

~ Vl

y~

;

Q ~RENAkDISEASE 9 O~RENALDISEASE II~ MINIMAL RENAL ABNORMALITIES

Figure, Pedigree. Family members with renal disease and unaffected genetic carriers are numbered. Table. Family members with history of renal disease

Family I member

Sex

Ear pits

Age (yr)

Initial symptoms

1-1

M

None

52

1ll-2 III-7

M M

Unilateral Unilateral

42 13

Ill-10

F

Bilateral

77

11I-11

F

Unilateral

77

Ill-13 1II-14 IV-3 IV-12 IV-19 IV-21

F M F F M F

None Bilateral Bilateral Bilateral None Unilateral

53 28 54 40 49 49

Proteinuria, Proteinuria, Proteinuria, Proteinuria, Proteinuria,

V-20

M

Bilateral

36

Proteinuria, age 14

V-41 V-43

M F

Bilateral Bilateral

25 24

Proteinuria, age 12 Proteinuria, age 15

V1-25

M

Unilateral

6

Renal osteodystrophy

showed residual enlarged nephrons and glomerulomegaly with segmental sclerosis and hyalinosis. The histologic features in patient V-43, in conjunction with radiographic studies, were compatible with simple hypoplasia and remnant kidney changes as well. Patients V-20 and VI-25 had changes similar to the other two patients, with focal and segmental glomerular sclerosis; however, the glomeruli were not enlarged. There were chronic tubular interstitial changes and prominent interstitial inflammatory infiltrates. VI-25 had small remnants of nephroblastomatous

Proteinuria, age 63

age age age age age

14 I0 21 17 19

Remarks Died of renal and pulmonary disease in 1884 Died of chronic renal failure Died of "chronic parenchymous nephritis" (death certificate) Cr 1.6 mg/dl Cr C1 27 ml/min Cr 1.5 mg/dl Proteinuria Died of chronic renal failure Died of chronic renal failure Died of chronic renal failure Died of chronic renal failure Atrophic right kidney Cr 2.0 mg/dl Proteinuria (1+) Cr 2.6 mg/dl BUN 51 mg/dl 24-Hour urinary protein 1.4 gm Cr CI 64 ml/min Died of chronic renal failure Cr 1.5 mg/dl Cr C1 51 ml/min Received a renal allograft in 1981

tissue. Fine structural and immunofluorescent patterns were nonspecific, and no evidence of glomerulonephritis or changes in the basement membrane characteristic of familial nephritis were present. That x 2 = 4 3 / / ~ <0.001 suggests that these malformations result from closely linked genes or2ossibly a single gene. Both traits appear to be inherited in an autosomal dominant fashion, with a penetrance of 79% (15 of 19 persons) for renal disease and 85% (22 of 26) for preauricular pits. If one gene is responsible for both malforma-

950

Clinical and laboratory observations

tions, there is variable expressivity, with 89% penetrance (26 of 29 persons). Family members 11-5, II-10, and Ili-8 did not have either preauricular pits or renal disease, but they would be obligate carriers of the gene. Results of the audiograms on family members V-20 and VI-25 were normal, and karyotyping on VI-25 was normal. DISCUSSION Preauricular pits and renal hypoplasia are known to occur in the branchio-oto-renal syndrome, which was first described by Melniek in 1975. 2.4 Additional features of the BOR syndrome include hearing loss, branchial fistulas or cysts, malformed ears, and lacrimal stenosis. Other anomalies may include a long narrow face, a deep overbite, and facial paralysis. Renal anomalies are present in approximately 66% of affected individuals, and range from minor dysplasia of one kidney to total bilateral aplasia. 4-8 Renal failure is estimated to occur in 6% of patients with renal involvement. We are not aware of families with BOR syndrome that have members with only preauricular pits and renal disease. Preauricular pits are small, blind-ended sinuses, usually located at or near the anterior limb of the ascending helix. They occur in up to 5.2% of blacks and 0.9% of whites, and are unilateral 75% of the time. 9 They are transmitted in an autosomal dominant fashion, with a variable penetrance of 85%. Ear pits alone have not been previously associated with renal disease. Our family does not appear to have BOR syndrome, because preauricular pits and renal disease are the only anomalies. The renal disease presents with proteinuria and is usually severe. Eleven (73%) of 15 family members have severe renal disease or have died from chronic renal failure. Males have been more seriously affected, and two

The Journal of Pediatrics June 1985

died at young ages. One boy (VI225) has a functioning renal allograft. These deaths have limited perpetuation of this syndrome by the most severely affected members. No renal aplasia has been diagnosed. In the general population, there is a high incidence of preauricular pits, which are small and often go unnoticed. We suggest that children with preauricular pits should be evaluated for proteinuria by routine urinalysis. Children with both ear pits and proteinuria should be evaluated thoroughly for evidence of serious renal disease. We thank Dr. Harold M. Nitowsky for assistance with statistical analysis, and Drs. Keith Holley and R. B. Wilson for allowing us to review pathologic material.

REFERENCES 1. McKusick VA: Mendelian inheritance in man. Baltimore, 1983, The Johns Hopkins University Press. 2. Smith DW: Recognizable patterns of human malformation, ed 3. Philadelphia, 1982, WB Saunders Co., pp 180-181. 3. Melnick M, Hodes ME, Nance WE, Yune H, Sweeney A: Branchio-oto-renal dysplasia and branchio-oto-dysplasia: Two distinct autosomal dominant disorders. Clin Genet 13:425, 1978. 4. Fraser FC, Ling D, Clogg D, Nogrady B: Genetic aspects of the BOR syndrome: Branchial fistulas, ear pits, hearing loss, and renal anomalies. Am J Med Genet 2:241, 1978. 5. Fourman P, Fourman J: Hereditary deafness in a family with ear pits (fistula auris congenita). Br Med J 2:1354, 1955. 6. Martins A: Lateral cervical and preauricular sinuses: Their transmission as dominant characters. Br Med J 1:255, 1961. 7. Cote A, O'Regan S: The branchio-oto-renal syndrome. Am J Nephrol 2:144, 1982. 8. Carrel R, Binshtock M, Abeliovich D, Bar-Ziv J: The branchio-oto-renal (BOR) syndrome: Report of bilateral renal agenesis in three sibs. Am J Med Genet 14:625, 1983 9. Bergsma D: Birth defects compendium, ed 2. New York, 1979, Alan R. Liss, p 377.

Congenital hypothyroidism caused by defective iodide transport R. M. Couch, M.D., H. J. Dean, M.D., and J. S. D. Winter, M.D. Winnipeg, Manitoba, Canada

From the Department of Pediatrics, University of Manitoba. Supported by the Children's Hospital of Winnipeg Research Foundation. Submitted for publication Sept. 4, 1984; accepted Nov. 20, 1984. Reprint requests: J. S. D. Winter, M.D., Section of Endocrinology and Metabolism, Children's Hospital, 678 William Ave., Winnipeg, Manitoba, Canada R3E OWl.

THE FIRST STEP in thyroxine synthesis is active transport of iodide from the extraeellular fluid into the thyroid cell, a process that operates against an electrochemical gradient and requires energy derived from oxidative metabolism. This same iodide-trapping mechanism is found also in the salivary glands and gastric mucosa. Defective iodide transport, causing goiter with or without hypothyroidism," has