Allgrove syndrome (isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2.5 and 8 years of age; however, two others became cortisol deficient after initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient-years of follow-up. Alacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant velo-pharyngeal incompetence. All showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In-vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes.

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We report on a child with a unique constellation of congenital anomalies suggesting a new syndrome. These consist of developmental delay; craniofacial abnormalities, including bilateral cataracts, ptosis, median nasal groove, malformed ears with associated neurosensory hearing loss; dental anomalies consisting of anomalous cusp morphology with unusual pointed extensions and delayed tooth eruption; short stature with marked delay in epiphyseal ossification; coronal clefts involving vertebrae T11-S2; and dislocated hips. A literature search and use of a computer-assisted syndrome-identification program failed to uncover an identical case.

We report on 6 (3 male, 3 female) Manitoba Indian children with hypertelorism and variable combinations of unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and anal anomalies. These children belong to 4 related families. The parents and 7 other sibs are clinically unaffected. The family histories are otherwise unremarkable. The presence of 2 major malformations in sibs and related individuals (with unaffected parents) suggests that this is a newly described pleiotropic autosomal recessive syndrome. The differential diagnosis includes cryptophthalmos syndrome and several other related malformation syndromes. Although multifactorial determination cannot be excluded, the inbred, isolated population and distribution make autosomal recessive inheritance more likely.

CODAS syndrome (MIM# 600373) is a rare multiple congenital anomalies syndrome. The disorder is highly distinctive with characteristic features consisting of developmental delay, cataracts, unusual enamel projections, overfolded and crumpled ears, epiphyseal dysplasia, and dysmorphic features (grooved nose, ptosis). To date, there have been two affected female children reported. The first was a Canadian girl of Mennonite descent, reported by our group, and the second was a girl from Brazil. The etiology and pattern of inheritance of CODAS is unknown. Herein we report a third affected child, a Canadian male infant of Mennonite ancestry. The child, now two years old, exhibits ptosis, cataracts, overfolded ears, grooved nasal tip, dental projections, developmental delay, and characteristic skeletal anomalies. The findings are characteristic for CODAS syndrome. All investigations including karyotype, metabolic screening, peroxisomal studies, and studies of cholesterol biosynthesis were normal. The underlying defect responsible for CODAS syndrome remains unknown. Many of the features suggest a possible underlying collagen gene defect. The fact that this child is the second child from the Manitoba Mennonite community, a genetic isolate, suggests the possibility of autosomal recessive inheritance. To date, there has not been a familial recurrence.