The association between cryptophthalmos and multiple congenital malformations has been well documented over the last century. Numerous authors have described cases as the cryptophthalmos syndrome, but recently reports of cases without cryptophthalmos have led several authors to use the eponymic designation Fraser syndrome. We have seen seven cases of cryptophthalmos syndrome, including three sib pairs. All presented with cryptophthalmos and bilateral renal agenesis in addition to other characteristic associated malformations. A literature review showed 124 cases in which 27 demonstrated isolated cryptophthalmos, while 97 showed a pattern of multiple congenital malformations. We selected four major and eight minor criteria which enabled us to classify 86 of those cases as having cryptophthalmos syndrome with 11 remaining unclassified. Cryptophthalmos demonstrates equal sex distribution, occurrence in sibs, consanguinity in families with more than one affected child, and lack of vertical transmission--strongly suggesting autosomal recessive inheritance. Isolated cryptophthalmos or cryptophthalmos sequence was sporadic in 16 cases and familial in 11. The familial cases occurred in three families and demonstrated vertical transmission. The pathogenesis of this syndrome is unknown. There are similarities to animal models of maternal vitamin A deprivation and defects in programmed cell death. Cryptophthalmos syndrome should be considered in the differential diagnosis of cases with multiple congenital malformations, especially when they are associated with renal agenesis, even in the absence of cryptophthalmos.

Orofacial clefts are among the most common types of birth defects, but their clinical presentation has not been well described in a geographically diverse US population. To describe the birth prevalence and phenotype of nonsyndromic clefts, we used data from the National Birth Defects Prevention Study (NBDPS), a multi-site, population-based, case-control study aimed at identifying genetic and environmental risk factors for birth defects. Included in the study were infants born during 1997-2004 with a cleft lip (CL), cleft lip with cleft palate (CLP), or cleft palate (CP). Infants with clefts associated with recognized single-gene disorders, chromosome abnormalities, holoprosencephaly, or amniotic band sequence were excluded. A total of 3,344 infants with nonsyndromic orofacial clefts were identified, including 751 with CL, 1,399 with CLP, and 1,194 with CP, giving birth prevalence estimates of 0.3, 0.5, and 0.4/1,000 live births, respectively. Among infants with CLP where cleft laterality was specified, about twice as many had unilateral vs. bilateral involvement, while for CL there were over 10 times as many with unilateral vs. bilateral involvement. Involvement was most often left-sided. About one-quarter of infants with CP had Pierre Robin sequence. Over 80% of infants had an isolated orofacial cleft. Among infants with CL or CLP, heart, limb, and musculoskeletal defects were most commonly observed, while heart, limb, and central nervous system defects were most common among infants with CP. Better understanding of the birth prevalence and phenotype may help guide clinical care as well as contribute to an improved understanding of pathogenesis.

Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0–1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non-white or younger than 20 years compared to white mothers or those age 25–29 years. The distribution of associated cardiac and extracardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy-Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left-right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.