American Journal of Medical Genetics 5:423-424 (1980)

Letter to the Editor: Autosomal Recessive Acrocephalosyndactyly Revisited

The recent publication by Goodman et al, “Acrocephalopolysyndactyly type IV: A new genetic syndrome in 3 sibs” [3] , has prompted us to reexamine the other autosomal recessive forms of acrocephalo-(2: po1y)-syndactyly, specifically, the Carpenter syndrome and the Summitt syndrome. (It should be noted that the possibility of X-linked recessive inheritance of Summitt syndrome cannot be discounted at this time; only 3 affected males have been reported, but the parents of Summitt’s patients were first cousins.)

At the time we wrote our case report 151, it seemed possible to distinguish between the Carpenter and the Summitt syndromes. Over 30 cases of the former have been published: Pfeiffer reported that there were at least 27 known cases in 1977 141, and Frias reported two, possibly three more cases in 1978 [2] . The Carpenter syndrome has been characterized by craniosynostosis, mental retardation, pre- or postaxial polydactyly, syndactyly , clino- brachydactyly, obesity, congenital heart disease, renal anomalies, hypogenitalism, and occasional short stature. The Summitt syndrome has been described in three individuals: two brothers in Summitt’s original family and one in our study [5] . The condition is charac- terized by craniosynostosis with normal intelligence, clinobrachydactyly, syndactyly, obesity, and neither polydactyly nor congenital heart defects.

Dr. Robert Gorlin has pointed out (personal communication, 1979) that this categor- ization is confounded by the family reported on by Goodman et al. These authors described three affected sibs with craniosynostosis not surgically corrected, with normal intelligence, clinobrachydactyly, syndactyly, and obesity; two with polydactyly and congenital heart disease (individuals 111-6 and 111-7); and one without congenital heart disease or polydactyly (individual 111-8). This family shows striking intrafamilial variability.

Another importnat new report is that of Frias et al, “Normal intelligence in two chil- dren with Carpenter syndrome” 121. Their patient l (a sporadic case) has “classical” manifesta- tions of Carpenter syndrome; however, she is of normal intelligence. Frias et a1 attribute the normal intelligence to early craniosynostectomy. The facial appearance of patient 2 suggests the Summitt syndrome. This patient had no congenital heart defect, but had polydactyly of hands and feet. He had a brother with craniosynostosis of all major sutures, proptosis, syndactyly of the fingers and polysyndactyly of the toes. That child died of bacterial men- ingitis after craniosynostectomy at age 5 months. The authors raise the question as to whether cranial operations will, in fact, prevent mental retardation. The patients reported on by Goodman et a1 and by Summitt did not have skull operations and are of normal intelligence. Thus, at present, we see no evidence that normal intelligence in the recessive acrocephalo-(+ po1y)-syndactylies can be attributed to such an operation.

These recent reports raise two important questions: 1) Can different autosomal re- cessive acrocephalo(+ po1y)-syndactylies be distinguished.on clinical grounds?; and 2) Can we predict from one affected member of a family what the clinical manifestations will be in a subsequently affected family member?

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424 Hall et a1

We suspect that several genetically distinct autosomal recessive acrocephalo-(+ po1y)- syndactyly disorders exist. However, at the present time we do not think that these can be distinguished firmly on clinical grounds. Goodman et a1 base the delineation of their new acrocephalosyndactyly syndrome (ACS Category IV), on facial appearance and normal in- telligence. The variable facial manifestations seen in the acrocephalo-(+ po1y)-syndactyly disorders most likely reflect the degree of cranial suture involvement, ie, which sutures are involved, to what extent they are synostosed, and how early in development the process began. It has been shown that the dominant forms of acrocephalosyndactyly are extremely variable and cannot be classified on the basis of suture involvement or the presence or ab- sence of mental retardation. Marked intrafamilial variability occurs [ I ] . Thus, it seems reasonable to assume that, in the autosomal recessive acrocephalo-(* po1y)-syndactylies, facial manifestations and mental retardation also will show intrafamilial variability and, therefore, not be useful for diagnosis and nosology. In this connection, the family reported on by Goodman et a1 is important because the intrafamilial variability demonstrates that a prediction of the type and severity of clinical manifestations of subsequent affected individuals in a family cannot be made with certainty.

(+ po1y)-syndactyly, it is difficult at this time to clearly delineate each disorder in this group of conditions. It is important that more familial cases be reported on, with care- ful attention directed toward intrafamilial variability.

Because of the paucity of reports of families with autosomal recessive acrocephalo-

Judith G. Hall,MD Head, Division of Medical Genetics Children's Orthopedic Hospital and Medical Center Associate Professor, Medicine and Pedia trics University of Washington School o f Medicine Susan D. Reed Genetics Associate University of Washington Clinical Genetic Services

Clifford J. SellS,MD Director, Clinical Training Unit Child Development and Mental Retardation Center University of Washington School of Medicine James W. Hanson,MD Department of Pediatrics University of lo wa Hospitals and Clinics

REFERENCES

1. Cohen hlM, Jr: An etiologic and nosologic overview of carniosynostosis syndromes. BDOAS 1 l ( 2 ) : 137-189, 1975.

2. P&dS JL, Felman AH, Rosenbloorn AL, Finkelstein SN, Hoyt WF, Hall BD: Normal intelligence in two children with Carpenter syndrome. Am J Med Genet 2: 191-199, 1978.

3. Goodman RM, Sternbcrg M, Shen-Tov Y, Bat-Miriam, Katznelson M, Hertz M, Roten Y: Acrocephalo- polysyndactyly type IV: A new genetic syndrome in 3 sibs. Clin Genet 15:209-214, 1979.

4. Pfeiffer R, Seeinann K, Tunte W, Gussone J , and Klemm E: Akrozephalopolysyndaktylie (Akrozep- halosyndaktylie, Typ I1 McKusick (Carpenter Syndrom) Bericht iiber 4 F d l e und eine Beobachtung des Typs von Marshall-Smith. Klin Paediat 189: 120-130, 1977.

5. Sells CJ, Hanson JW, Hall JG: The Sumniitt syndrome: Observations on a third case. Am J Med Genet 3:21-33, 1979.