1 Renal Unit, Glasgow Royal Infirmary, 2 Medical Unit, Glasgow Royal Infirmary and 3 Renal Unit, Stobhill Hospital, Glasgow
Case report
A 30-year-old female was referred with hypertension and renal failure. She had no personal or family history of renal disease although both her mother and sister were hypertensive (II5 and III3 respectively in family tree, Figure 1). Blood pressure was 196/116 mmHg with grade II retinopathy. Both kidneys were palpable and urine analysis revealed protein+only. Serum creatinine was 160 µmol/l with 24 h urine albumin excretion of 106 mg. Ultrasound showed both kidneys to be enlarged at 20 cm with multiple cysts (average diameter 2 cm). No hepatic or pancreatic cysts were seen. During childhood she had treatment for congenital defects including correction of a bifid right great toe and excision of a fibrocyst below her tongue. At the age of 12 she was diagnosed as having oro-facial-digital (OFD) syndrome with documented features at this time being: lobulate tongue with partial cleft palate (Figures 2
and 3
); antimongaloid slanting epicanthus; strabismus; hypoplasia of the left nostril; syndactyly affecting all fingers; short proximally placed thumbs; incurved index, ring and fifth fingers with broad middle finger (Figure 4
); abnormal feet with broad great toes and IIIII syndactyly. She was also diagnosed as having epilepsy and a brain CT scan had revealed an absent posterior corpus callosum.
Chromosome analysis confirmed a normal female karyotype. The clinical features at that time were felt to represent the autosomal recessive variety (Mohr Syndrome, OFD Type II) of OFD which was supported by the lack of family history.
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Due to the presence of polycystic kidneys in her mother, the patient was considered to have X-linked dominant inheritance of polycystic kidneys in association with type 1 OFD.
Discussion
In recent years our understanding of the genetics of polycystic kidney diseases has improved with the identification of the common genes for autosomal dominant polycystic kidney disease (ADPKD) -PKD1 and PKD2 [1,2]. The polycystic phenotype may arise from several disparate genetic abnormalities and there are several other candidate PKD genes. The picture is further complicated by the fact that the genes involved in expression of this phenotype may require interaction with other genetic and/or environmental factors before disease is clinically manifest. The apparent clinical prevalence of ADPKD has been estimated to be 50% of the expected gene frequency [3], suggesting that the genetic first hit (producing the polycystic phenotype) is insufficient to produce clinically manifest disease. Nearby genes may influence disease expression (contiguous gene syndrome) as has been suggested for the tuberous sclerosis (TS) gene locus on chromosome 16 (TSC2) [4], leading to renal failure in childhood. Similarly, if polycystic kidneys are inherited in association with a defect in a tumour suppression gene, such as the von Hippel Lindau (VHL) gene locus on chromosome 3, the risk of renal cell carcinoma may be increased [5].
OFD syndromes are rare inherited disorders that are usually diagnosed in childhood. Two types of syndrome are described: OFD type I and OFD type II (Mohr's syndrome), which are thought to be inherited in an X-linked dominant and autosomal recessive pattern respectively [6]. In OFD type I the X-linked dominant mode of inheritance passes the disorder on to females but is lethal in male children. In addition to having documented features of OFD, our patient had partial agenesis of the corpus callosum, which has previously been described in OFD type I with polycystic kidneys [7]. While there is considerable overlap in the clinical features of the type I and II syndromes, the presence of polycystic kidneys and agenesis of corpus callosum are thought to be specific to the type I syndrome. Despite incomplete information on all family members, the mode of inheritance in this family appears to be X-linked dominant as neither spontaneous mutation nor autosomal recessive inheritance can account for the presence of polycystic kidneys in the mother. The rate of spontaneous miscarriage is also consistent with X-linked dominant inheritance of a condition that is fatal in male children. The lack of characteristic extrarenal features in the mother does not exclude OFD as this may represent failure of expression of this phenotype due to incomplete penetrance (OFD sine OFD). Inheritance of polycystic kidneys without extrarenal manifestations has been documented in both TS and VHL and reappearance of extrarenal manifestations in subsequent generations has also been observed [8,9].
Genetic analysis of patients with TS and polycystic kidneys helped to identify the PKD1 gene locus as the loci are in close proximity on chromosome 16. With several reports of an association between OFD type I and polycystic kidneys, it is possible that a gene for X-linked dominant inheritance of polycystic kidneys lies close to the recently identified locus for OFD type I on the X chromosome [10]. The renal prognosis for polycystic kidneys associated with OFD type I is variable (in the cases described the mother had a normal creatinine at the age of 62 while the daughter had significant renal impairment at age 32) and it is possible that contiguous gene interaction exists between the two loci. Identification of these gene loci and their resultant proteins may help add to our expanding knowledge of renal cyst formation.
Teaching point
OFD syndrome type I is an X-linked dominant condition that may be associated with polycystic kidneys. We suggest that all patients diagnosed in childhood as having OFD should be screened for polycystic kidneys and that family members of patients with OFD and polycystic kidneys should undergo screening irrespective of the presence or absence of extrarenal features.
Notes
Supported by an educational grant from
Correspondence and offprint requests to: Dr Kevin McLaughlin, Division of Nephrology, Foothills Hospital, 1403 29th Street N.W., Calgary, Alberta T2N 2T9, Canada.
References