American Journal of Medical Genetics 33:479-482 (1989)

A New Autosomal Recessive Disorder Resembling Weaver Syndrome Ahmad S. Teebi, T.S. Sundareshan, Mousa Y. Hammouri, Sadika A. Al-Awadi, and Qasem A. Al-Saleh Kuwait Medical Genetics Centre, Maternity Hospital (A.S. T.,T.S.S.,S.A.A.), Pediatric and Dermatology Departments, Sabah Hospital (M. Y.H.,Q.A.A.), Kuwait

Most reported cases of Weaver syndrome are sporadic, and the mode of inheritance is still unclear. We describe two (male and female) sibs born to consanguineous Bedouin parents with manifestations resembling Weaver syn- drome. Both sibs had accelerated growth of prenatal onset, hypotonia, psychomotor retar- dation, excess loose skin, peculiar craniofacial and acral anomalies, dental dysplasia and/or serrated gums, joint laxity, and hoarse low- pitched cry. One of them had an accelerated harmonic skeletal maturation. Differentiating features from Weaver syndrome are discussed, and autosomal recessive inheritance is sug- gested.

KEY WORDS: connective tissue disorder, ec- todermal dysplasia, new syn- drome, overgrowth syndrome

INTRODUCTION The original description of Weaver syndrome (WS)

[Weaver et al., 19741 included accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camp- todactyly. Further reports of patients, mostly as sporadic occurrence, have suggested that WS is a distinct entity clinically distinguishable from other overgrowth syn- dromes [Gemme et al., 1980; Weisswichert et al., 1981; Farrell and Hughes, 1985; Hall, 1985; Ardinger et al., 19861.

Despite the increasing number of reported cases, the genetics of WS remains unclear since there is no evidence of well-documented familial instances. Here, we report on two sibs of consanguineous parents with a probably “distinct disorder” reminiscent of Weaver syndrome.

Received for publication October 26, 1988; revision received

Address reprint requests to Dr. A. S. Teebi, P.O. Box 36660 March 20, 1989.

Raas, 24757 Kuwait.

0 1989 Alan R. Liss, Inc.

CLINICAL REPORT Patient 1

Patient F.H.F., the proposita, was examined at age 10 days (December 1984) because of abnormal facial ap- pearance. She was born normally at term after an unre- markable pregnancy, weighing 4,450 g without neonatal problems. On examination, she looked large, slightly hypotonic with an apparently large head weight, 4,500 g; length, 55 cm; and OFC, 38.2 cm. She also had a large forehead, round face, slightly bulging eyes, with shallow orbits, antimongoloid slant and depressed supraorbital ridges, wide palpebral fissures, ocular hypertelorism and semilunar creases below eyes, short nose with depressed nasal bridge, long philtrum, large mouth, serrated gums, relatively small, folded, apparently low-set ears with lack of cartilage in some parts of the ear pinnae and fleshy ear lobule, relative micrognathia, short neck with redun- dant skin of face and neck, and distended abdomen with umbilical hernia but no organomegaly. Hands showed prominent finger-tip pads, mild interdigital webbing, short 5th finger, with severe clinodactyly, and unusual dermatoglyphics with bilateral incomplete single palmar creases and hypoplastic dermal ridges. Feet showed cli- nodactyly of the toes and long great toe. The cry was hoarse, monotonous, and low pitched. Results of routine hematological and biochemical investigations and thy- roid function tests were normal. Skeletal radiographs showed no gross abnormalities, and bone age was normal. G-banded chromosomes were normal.

During the first year, she showed delayed psychomotor development, and by the end of 1 year, she could only sit without support. Her weight was 14 kg; length, 85 cm; and OFC, 50 cm (all above the 97th centile). She had almost the same characteristics noted at birth including the characteristic cry in addition to a prominent metopic suture, the small pointed nose with anteverted nostrils, lax hand joints, and mild hypotonia. Bone age was nor- mal.

At age 18 months, she started to say single words and tried to stand. He teeth were dysplastic, and sweating was normal. At age 27 months, she started to walk and her dysplastic teeth started to exfoliate. Her facial anom- alies became more prominent, and bone age was slightly advanced (3-4 years). Her weight was 19.5 kg; height, 96 cm; and OFC, 53 cm (all above the 97th centile). CT scan

480 Teebi et al.

Fig. 1. Patient 1 (42 months). Fig. 2. Patient 2 ( 2 months).

of the head showed mild cerebral atrophy, mild dilatation of the 3rd and lateral ventricles, normal 4th ventricle, widened basal cisterns, and Sylvian fissure and subarach- noidal space in the bifrontoparietal region. Following scan showed no evidence of obstruction.

At age 42 months (Fig. 1) her weight was 22.5 kg; height, 108 cm; and OFC, 53.5 cm (all above 97th centile) with almost all teeth exfoliated. She had redundant skin over her entire body. However, when the skin was pulled out in a fold and then released, i t sprung back into the original position. Her scalp hair was thin and hypopig- mented. She developed pes planus, and her gait was unsteady and wide based. Vision and hearing were nor- mal. Long bone radiographs showed slightly widened metaphyses, and bone age was between 5-6 years.

At age 50 months, she weighed 24.5 kg and her height was 117 cm, and OFC, 54 cm (> 97th centile). Her inner canthal distance (ICD) was 4 cm and interpupillary dis- tance (IPD) 7 cm (> 97th centile). Radiographs showed an accelerated harmonic osseous maturation. The capi- tate, hamate, and triquetral bones were well developed. The trapezium that usually appears at the age of 6 years was seen. The head and the lower end of the radius were also seen (5-7 years). I& was 70 (Stanford-Binet intelli- gence scale).

Patient 2 Patient S.H.F., a brother of patient 1 (Fig. 2), examined

at age 2 months (February 1988) a few days after being

operated on for intestinal obstruction due to intussuscep- tion. Pregnancy and delivery were unremarkable, and his birth weight was 3,950 g. On examination, he weighed 4,200 g, and had a length of 59 cm and OFC of 38 cm. Manifestations were similar to those of patient 1; in addition, he had swallowing difficulty, hyperelastic skin, large ear with fleshy ear lobule, hypertrophic serrated gums, semilunar crease a t the finger-tip pads, inguinal hernias and bilateral talilpes equinovarus, and marked hypotonia. Skeletal radiographs showed slightly widened metaphyses and normal bone age. Thyroid function tests were normal.

At age 13 months, he weighted 5.9 kg, height 68 cm (< 3rd centile), and OFC, 46.6 cm (50th centile). His ICD was 3.2 and IPD 5.5 (> 97th centile). He showed mod- erately severe psychomotor retardation. Contrary to his sister, his radiographs were suggestive of a mild degree of osseous immaturation. The lower femoral and upper tibia1 epiphyses showed irregular outlines. Also, the cap- itate and hamate were very small for his age. (Manifes- tations are compared to patient 1 in Table I).

Family Data Parents were second paternal cousins of Bedouin ori-

gin. The father and mother were 30 and 19 years old, respectively, when seen in 1984. They looked normal with average height and weight. Apart from the two patients, they have no other children. The father suffers from a presumably autosomal recessive childhood onset

Recessive Weaver-like Syndrome 481

TABLE I. Manifestations of the Two Sibs ~~ ~

Manifestations Patient 1

(proposita) Patient 2 Sex Age (last assessment) Prenatal growth excess Postnatal growth excess Accelerated osseous maturation Psychomotor retardation Craniofacial anomalies

Thin hypopigmented hair Large forehead/frontal bossing Prominent metopic sutures Round large face Shallow orbits/depressed supraorbital ridges Ocular hypertelorism Antimongoloid eye slant/wide palpebral fissures Short nose Depressed nasal bridge Long grooved philtrum Large mouth Dysplastic teeth/serrated gums Relative micrognathia Ear anomalies Short neck/broad neck base

Acral anomalies Prominent finger-tip pads Simian creases

Short 5th finger/clinodactyly 5th finger Mild interdigital webbing Joint laxity Long 1st toe/clinodactyly of the toes Talipes equinovarus/pes planus

Abnormal voice and cry (hoarse, low-pitched) Others

Hypotonia Hernias (umbilical, inguinal) Excess loose skin/hyperplastic skin Swallowing difficulty Wide metaphyses Unsteadv wide-based gait

F 50 months

+ + +

+ (IQ 70)

+ + + + + + + + + + + + + + + + +

(incom- plete)

+ (severe) + + + + +

M 13 months +

- -

++ (DQ 35)

+ + + + + + + + + + + + +

-

+ +

+ (mild) + + + + +

sensorineural deafness of moderately severe degree. He has a brother with deafness in addition to three normal brothers and four normal sisters with first-cousin par- ents. No other relatives had a condition similar to the proposita and her brother.

DISCUSSION Since 1974, at least 21 WS patients have been de-

scribed [Moreno and Kirkland, 1974; Weaver et al., 1974; Bosch-Banyeras et al., 1978; Gemme et al., 1980; Ma- jewski et al., 1981; Weisswichert et al., 1981; Meinecke et al., 1983; Amir et al., 1984; Dawood et al., 1985; Farrell and Hughes, 1985; Hall, 1985; Ardinger et al., 19861. There are 15 males and six females. Consistent clinical manifestations include prenatal and postnatal over- growth and accelerated dysharmonic osseous maturation, psychomotor delay, hoarse low-pitched cry, looseness of skin and hernias, hypertonia, and the characteristic cra- niofacial acral abnormalities. These include broad fore- head, large ears, ocular hypertelorism, prominent or long

philtrum, relative micrognathia, camptodactyly and/or clinodactyly, prominent finger pads, wide distal long bones, and foot deformities. The combination of these manifestations make WS a distinct entity clinically dis- tinguishable from Marshall-Smith syndrome and other overgrowth syndromes [Fitch, 1980; Ardinger et al., 19861.

Our patients showed many of the manifestations of WS. Thin hair, antimongoloid slant of palpebral fissures, and swallowing difficulties present in either or both of our patients were reported in WS [Fitch, 19851. Unusual for WS patients, the proposita has an accelerated but harmonic osseous maturation. Also, patient 2 had osseous immaturity. On the other hand, wide palpebral fissures, shallow orbits, serrated gums, dental dysplasia, interdi- gital webbing, and joint laxity, which are not known in WS, were found in our patients.

The genetics of WS is still unclear. Its mostly sporadic occurrence may point to a dominant fresh mutation. The occurrence of conditions resembling WS in sibs has been

482 Teebi et al.

reported twice. We agree with Fitch [1985] that the diagnosis of WS cannot be confirmed in the male and female sibs reported by Roussounis and Crawford [ 19831 because of insufficient information in their paper. On the other hand, Jalaguier et al. [1983] described two sibs (a male and a female) with overlapping manifestations of Marshall-Smith and WS and suggested that these syn- dromes are a single entity. We do not think that the diagnosis of WS can be confirmed in their patients.

In this report, parental consanguinity and affected male and female sibs strongly suggests autosomal reces- sive inheritance. I t seems, however, that our two patients have distinct overgrowth disorder resembling WS with some elements of ectodermal dysplasia. The craniofacial and acral anomalies, loose hyperelastic skin, and joint laxity are consistent in both of them, whereas psycho- motor development, hypotonia, postnatal growth, and osseous maturation are highly variable. This disorder seems to be clinically distinct from WS and other over- growth syndromes. More reports will help further char- acterization and better understandability of the nature of underlying pathology.

ACKNOWLEDGMENTS

We thank Dr. A.G. Al-Ansari, FRCR, for radiological evaluation and Mrs. Regina Ratos for secretarial assist- ance.

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