Distal limb deficiencies, oral involvement, and renal defect: Report of a third patient and confirmation of a distinct entity

INTRODUCTION

In 1987, Buttiens and Fryns reported on two sibs with distal limb deficiencies and oral involvement and suggested that they had a new autosomal recessive syndrome with mental retardation, myopia, and hypoplastic kidneys as additional manifestations. The present patient has a similar condition and gives evidence that the phenotype is a specific clinically recognizable syndrome.

CLINICAL REPORT

A.S. is the second child in a sibship of three children. His parents and two sisters are normal. The parents are not consanguineous and family history is not contributory. At the time of the boy's birth, the mother was 22 and the father 28 years old. The pregnancy was uneventful and the boy was born at a gestational age of 37 weeks. Birth weight was 2,700 g, length 47 cm, and head circumference (OFC) 35 cm. Severe congenital anomalies were noted immediately, including distal limb defects, micrognathia, cleft palate, and nystagmus. Radiological examination of the limbs showed normal long bones, the presence of two metacarpals and one ulnar finger with two phalanges on both hands, and the presence of one metatarsal and one phalanx in the feet. The tarsal and carpal bones were not completely ossified at that time. Abdominal ultrasound disclosed bilateral renal hypoplasia (no exact measurements available). Results of further investigations, including cerebral CT scan, cerebral MRI, and karyotype, were normal. The child developed severe myopia, slowly progressive renal failure, and chronic serous otitis media, causing a bilateral hearing loss of 40 dB.

The child was reexamined at the age of 4 9/12 years. His height was on the 10th centile, weight between the 3rd and 10th centile, and OFC on the 25th centile. He had micrognathia, a small tongue, and mild maxillary hypoplasia. The limb defects involved the four limbs and were symmetrical (Figs. 1-3). His psychomotor and intellectual development were appropriate for age. Vision was partially corrected with glasses. Renal function continued to decrease slowly (creatinine clearance of 29 ml/min/1.73 m²), and he is a candidate for kidney transplantation.

DISCUSSION

No classification system of limb and oromandibular anomalies has been accepted unanimously and the nosology of these entities remains difficult. In the classification system of Hall [1971], hypoglossia is a constant finding and the presence or absence of other oral anomalies and limb defects lead him to divide the oromandibular-limb hypogenesis syndromes into five categories. However, Herrmann et al. [1976] separated patients with orofacial anomalies and limb deficiencies into only two groups, namely, Hanhart syndrome and Poland-Möbius syndrome. Others [Goodman and Gorlin, 1997; Gorlin et al., 1990; Kaplan et al., 1976] preferred to speak about the “community of face-limb malformation syndromes” or “oromandibular-limb hypogenesis syndrome” and reduced this group of syndromes to one descriptive denominator. Boutsen et al. [1987] even represented the “different” entities graphically, demonstrating their clinical overlap. Nevertheless, this phenotypic resemblance is not synonymous for causal homogeneity, and it is likely that the oromandibular-limb hypogenesis syndromes represent a spectrum of disorders originating from different mechanisms. Several causal hypotheses have been proposed, including drug ingestion during pregnancy [Bökesoy, 1983; Pauli and Greenlaw, 1982], gestational hyperthermia [Graham, 1988], intrauterine trauma [Alexander et al., 1992], vascular disruption [Van Allen, 1981], and genetic factors [Gorlin et al., 1990]. Several of the genes involved in human limb formation are known [Innis and Mortlock, 1998] and it is not inconceivable that dysfunction of some of them also affects the morphogenesis of other parts of the body.

The sibs reported by Buttiens and Fryns [1987] showed some degree of mental retardation and the boy presented severe myopia and oligomeganephronia. They differed from previously described patients in the type of limb defects, which were symmetric paraxial radial/preaxial defects instead of a total distal transverse reduction defect. Their limb deficiencies were also different from those seen in other cases in which acral and renal malformations are associated (the acrorenal syndromes). In these syndromes the limb anomalies consist merely of ectrodactyly, which is a defect of the central rays.

The brother had absence of both radii and the ulnae were bowed and hypoplastic in the distal half. Rudimentary bones were present at the tip of the forearm stumps. In the feet, there was synostosis of a rudimentary calcaneus and talus and a short tubular bone. The limb anomalies of the sister were characterized by deformation and bowing of the distal radii, the presence of small carpi, and absence or hypoplasia of several metacarpals. Only the 5th metacarpals and phalanges were normal. A similar pattern of anomalies was seen in both feet.

We found that the described limb deficiencies in these sibs resembled closely the ones observed in the boy of the present report. The main difference between the three patients is that the male sib of Buttiens and Fryns [1987] has complete absence of both radii, whereas the two other patients have only partial involvement of the radial ray. However, this should be regarded as a variable expression of the same causal mechanism.

We conclude that the present patient has—besides his normal intellectual development—a very similar condition to the sibs in the report of Buttiens and Fryns [1987].