Fifty years of recognizable patterns of human malformation: Insights and opportunities

Abstract

Now in its 7th edition, Smith's Recognizable Patterns of Human Malformation was first published in 1970. This 1st edition comprised 135 "dysmorphic syndromes of multiple primary defects" and 12 "single syndromic malformations resulting in secondary defects." Of the former, other than a few chromosomal and environmental disorders, most were heritable conditions of then unknown etiology. In 2021, the majority of these conditions are now "solved," a notable exception is Hallermann-Streiff syndrome. The "solved" conditions were typically clinically delineated decades prior to understanding the underlying etiology, which rarely required recent technologies such as exome sequencing (ES) to elucidate. The 7th edition includes nearly 300 syndromes, sequences, and associations. An increasing number of conditions first appearing in the latest editions are sporadic, with many solved using either array CGH or ES. We have reviewed all syndromes that have appeared in "Smith's" with a focus on inheritance, heterogeneity, and year and method of etiologic discovery. Several themes emerge. Genetic heterogeneity and pleiotropy of genes are frequent. Several of the currently "unresolved" syndromes are clinically diverse such as Dubowitz syndrome. Multiple recurrent constellations of embryonic malformations, with VACTERL association as a paradigm, are increasingly likely to have a shared pathogenesis requiring further study.

NAD+ deficiency in human congenital malformations and miscarriage: A new model of pleiotropy

“…There are many human malformations, which occur both individually and in combination, for which a mechanism, genetic or otherwise, has yet to be identified (Innes & Lynch, 2021). Historically, there have been hypotheses presented to identify potential mechanisms for these conditions.…”

“…Despite advances in genetic testing, including chromosomal microarray, exome sequencing, genome sequencing, and newer approaches including transcriptome and methylation analyses, there remains a group of conditions which include anomalies originating in early embryonic development for which a mechanism, genetic or otherwise, has yet to be identified (Innes & Lynch, 2021). In an effort to generate study of these conditions, some members of this group were labeled Recurrent Constellations of Embryonic Malformations (RCEM) including pentalogy of Cantrell (POC), limb-body wall complex (LBWC), omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex, vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL), oculoauriculovertebral spectrum (OAVS), and Mullerian duct aplasia-renal anomalies-cervicothoracic somite dysplasia (MURCS; Adam et al, 2020).…”

Hallermann-Streiff syndrome diagnosed in the seventh decade of life

“…Given that HSS is a rare human malformation for which the molecular/genetic basis of disease have not been determined, 14 HSS is still diagnosed based on the clinical features. Previously reported patients with HSS were all infants, 5 , 6 children, 2 , 7 , 8 , 9 or at the oldest, young adolescents.…”

Frequency of various types of gastrointestinal abnormalities in patients with Down’s syndrome.

“…Hypotension, lymphedema, thickening of nuchal cord, epicanthi folds and Simian crease are the striking features of Down syndrome at birth. 8 It is imperative to screen the life-threatening complications of Down syndrome before discharge after birth as it accompanies various complications including cardiovascular, pulmonary, gastrointestinal and ENT etc…. among all of the above complications there's increased frequency of gastrointestinal problems.…”