3'Med Genet 1997;34:813-816 A syndrome including thumb malformations, microcephaly, short stature, and hypogonadism Joel Zlotogora, Judith Dagan, Adnan Ganen, Mazen Abu-Libdeh, Ziva Ben-Neriah, Tirza Cohen Abstract We report on eight patients from seven different families affected with a syn- drome which includes thumb defects, short stature, microcephaly, and mental retardation. Most of the patients had additional malformations, in particular amenorrhoea and azoospermia in the adults. There were no haematological manifestations and the chromosomes were normal without evidence ofbreakage even after stimulation. In five of the cases the probands' mother received hormonal treatment before or at the beginning of her pregnancy or both. The syndrome may be inherited as an autosomal recessive trait since the pa- tients included both males and females and their parents were related in most cases. In addition, supporting this possibility, they all originated from a small village which may be considered as an isolate. However, in all cases but one, only one person was affected in each fam- ily and there was a significant apparent excess of healthy sibs of the probands. These observations may be the result of the variability of the syndrome or a more complex type ofinheritance. (7 Med Genet 1997;34:813-816) Keywords: hypogonadism; Fanconi anaemia, micro- cephaly; thumb malformations Department ofHuman Genetics, Hadassah University Hospital, Hadassah Medical School, Hebrew University, Jerusalem, Israel J Zlotogora J Dagan Z Ben-Neriah T Cohen Kupat Holim Sick Fund, Israel A Ganen M Abu-Libdeh Correspondence to: Dr Ziotogora, Hadassah University Hospital, POB 12000, Jerusalem il 91120, Israel. Received 14 January 1997 Revised version accepted for publication 12 May 1997 Congenital malformations of the thumbs are variable and often bilateral. They may include triphalangism, hypoplasia, aplasia, or polysyn- dactyly. In some cases the malformations are mild, such as short, large, or proximally placed thumbs. Malformations of the thumbs may be found together with other radial defects, such as hypoplasia or aplasia of the radius, or with other malformations, often as part of known syndromes.' Among the most frequent organs involved together with the thumbs are the heart, urinary tract system, skeleton, and blood. The VACTERL association includes radial ray deformities, defects of the vertebrae, anal atresia, tracheo-oesophageal fistula, renal malformations, and congenital heart defects. Many syndromes associated with thumb mal- formations are included in 1 13 entries in OMIM.' In some of the syndromes with absence of thumbs or radial rays or both, the major additional features are orofacial malfor- mations, such as in Nager syndrome and Juberg-Hayward syndrome, or cardiovascular malformations, such as in Holt Oram syn- drome. In other syndromes blood dyscrasia is the pathognomonic feature, such as in Fanconi anaemia and the syndrome of thrombocyto- penia and absent radius (TAR).' We report here on a group of patients presenting with thumb malformations together with microcephaly, mental retardation, short stature, and hypogonadism and discuss possi- ble diagnosis and aetiology. Patients and methods All the patients originated from a small Muslim Israeli Arab village located near Jerusalem, fully integrated into the life of the State of Israel. Almost all the inhabitants can trace their ancestry back less than 10 generations from a very small number of founders. The village includes three large kindreds which each represent almost 25% of the household units (AR, JA, and IB) and three smaller kindreds (OT, AK, and SA). The inhabitants of the vil- lage are devout followers of their Islamic tradi- tions and have maintained their isolation mainly by marriages within the family or within the village or both. In 1994, there were approximately 6000 inhabitants of the village. Malformations of the thumbs were diag- nosed in the genetic clinic at Hadassah Medical Center in seven patients originating from the village. In addition, a severely retarded female living in the village, never seen in the genetic clinic, was examined because of the similarity of her symptoms to those of the other patients. She had a proximal insertion of both thumbs with mild hypoplasia of the left thumb and therefore she was also included in the present study (OT F). A clinical summary of the eight patients is given in table 1 and the pedigree of the families in fig 1. The thumb malformations were variable, often different in the right and left thumb in the same patient as well as from patient to patient, and included aplasia, hypoplasia, and malposi- tion. None of the patients had large or bifid thumbs, none had radial aplasia or hypoplasia, and their toes were normal. One patient was born with severe hydrocephalus with alobar holoprosencephaly and died in infancy. The other seven patients were affected with various degrees of mental retardation and had signifi- cant microcephaly (less than 2 SD for age). Four of the adult patients are mildly retarded, but integrated into daily life, and the other is severely retarded. Both adult males are working and one of them is married; the three adult females are single and helping at home. All but 813 o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jm g .b m j.co m / J M e d G e n e t: first p u b lish e d a s 1 0 .1 1 3 6 /jm g .3 4 .1 0 .8 1 3 o n 1 O cto b e r 1 9 9 7 . D o w n lo a d e d fro m http://jmg.bmj.com/ Zlotogora, Dagan, Ganen, Abu-Libdeh, Ben-Neriah, Cohen ._ tr-4 oo 00 - 0 r u u e M 4 m ; a c).; U 0, E ° E i E S C+ e BED + b c) 0 ~ 0 O C)0 M. - ~0 00 v c - + CO3 CO 0) 0 v C 0° 0)C,; ) -1: -C 00 °-4 + + Ew4 EC-. U cl 0 .0 0 0(I. :O.°>e unCc+l 0. 02 COZ r. E.b ) c. su - 0 .5. S ,c .0 3 CO u = *PcoE U rC- r)C .0=. S one patient had a low or very low birth weight; short stature was present in all the patients and the adults reached a height between 125 to 145 cm. The three adult females had primary amenorrhoea. In one of them, an abdominal ultrasound was performed in which the ovaries were not seen. The male patient who was mar- ried was infertile because of azoospermia. None of the patients had any haematological problems and no malignancies have been diag- nosed. In all the patients studied the chromo- somes were normal and there was no induced chromosomal breakage after DEB stimulation performed in two unrelated patients. Fertility problems were present in four of the patients' mothers. They received hormonal treatment (details on the type of treatment were not available to us) before and during the pregnancy of the affected patient. In three of these women the hormonal treatment was given only for the pregnancy of the proband; in the fourth, the mother also received treatment in another pregnancy from which a normal child was born. In a fifth family, the pregnancy was unwanted and the patient's mother took medication to have an abortion (JA F). Three of the families were from the JA kindred (four patients), two from the AR kindred, and two from the OT kindred. In six out the seven families the probands' parents were closely related and in the last family the parents did not know of any relationship but originated from the same kindred (JA). Among the total of 40 children in the seven different families, there were two affected sibs in only one family (JA H and S). On the assumption that the syndrome was inherited as an auto- somal recessive trait, eight of the 33 probands' sibs would have been expected to be affected instead of only one observed (X2=8.5, p<0.0 1) . .0 CPo r. 0 0 S. 0 70 0 ~cr sz C' v v -0 cn cX Eu 'A u -t co u 03 au . 1 Discussion The similarity between the patients was evident, in particular when they were all exam- ined over a short period of time, and we have no doubt that they are affected with the same syndrome. Among the numerous syndromes including thumb/radial malformations searched for in OMIM, LDDB, and POS- SUM, most could be easily ruled out. In com- paring those syndromes in which more than one family with affected patients was reported, the main differential diagnosis includes Fan- coni anaemia and the Juberg-Hayward syn- drome, since in both syndromes the major malformations overlap those present in our patients (table 2). All the malformations found in our patients have been reported in patients with Fanconi anaemia and the variability from one patient to another is similar in both syndromes.3 The major clinical differences are the rarity of mental retardation in Fanconi anaemia and the absence of bone marrow fail- ure in our patients. It should be noted that recently two adult sibs affected with Fanconi anaemia were reported with microcephaly, hypogonadism, and mental retardation.4 The sister had no haematological manifestation or malignancy up to the age of 56 years, and Fan- coni anaemia was diagnosed by the presence of 0 0 v t ;2 _t Q. _^1 814 -. 0 . 6't + o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://jm g .b m j.co m / J M e d G e n e t: first p u b lish e d a s 1 0 .1 1 3 6 /jm g .3 4 .1 0 .8 1 3 o n 1 O cto b e r 1 9 9 7 . D o w n lo a d e d fro m http://jmg.bmj.com/ 815Thumb malformations, microcephaly, short stature, and hypogonadism 1948 1945 i- b d 6 b~ b 2 JAA 1971 AR A 1995 OT B 19951930 1933 6 b 6