Hemiscrotal agenesis: a novel phenotype of a rare malformation

Scrotal agenesis either bilateral or unilateral is considered to be an extremely rare developmental anomaly of the scrotum [8]. During fetal life, scrotal development starts by formation of labioscrotal folds on both sides of the urogenital folds in the 7th embryonic week. Testosterone reaches its peak during the 10th gestational week and is converted by the enzyme 5-alpha reductase into more potent dihydrotestosterone (DHT), which induces virilization of the external genitalia [9]. At the 16th gestational week, fusion of the labioscrotal folds occurs to form the scrotum [1, 3].

Despite that the embryological development of the external genitalia is well known, the exact embryological etiology of scrotal agenesis is still unknown. Maldevelopment of labioscrotal folds is considered to be the cause of scrotal agenesis by either mechanical or endocrine disorders [8]. It is also proposed that localized partial androgen insensitivity and 5a-reductase type 2 deficiency may be the cause. However, enough DHT is produced to prevent labia formation without stimulation of scrotal development, as evidenced by the presence of the midline raphe [1‐3, 9].

Although the number of HSA cases reported in literature is scarse, the clinical phenotype varies. Three of the reported cases were associated with ipsilateral cryptorchidism [2, 4, 5] and the remaining 3 had complete testicular descent [1, 3, 6]. Moreover, scrotal agenesis may present as an isolated anomaly or may be associated with a variety of other congenital defects such as face anomalies, growth retardation, cardiac anomalies, anterior ectopic anus, digit anomalies [1, 4, 10]. Of the reported cases with HSA, 1 patient had PHACE syndrome, 1 patient had Van der Woude syndrome, and 1 had cutis marmorata telangiectatica congenita, and hydronephrosis due to vesicoureteral reflux [3, 6, 7]. Only 1 patient had an island of scrotal tissue in the pubic tubercle region, in addition to HSA [4].

As regards limb anomalies associated with atypical genitalia, few patients were shown to have mutation in human gene HOXA13 and HOXD13. HOX genes encode a family of transcription factors that play a major role in the development of the central nervous system, axial skeleton, gastrointestinal and urogenital tracts, external genitalia, and limbs during embryonic development. Mutations in these genes cause a wide range of malformations. The most common amongst these malformations are hand-foot-genital syndrome caused by HOXA13 gene mutation, and synpolydactyly caused by HOXD13 mutation. The severity of the phenotypic manifestation of these diseases is variable, and depends on the exact mutation type [11‐13]. Interestingly, the presence of HAS along with unilateral cerebellar hypoplasia and unilateral monadactylus limb possibly suggest a vascular disruptive origin and according to Stephens, a possible mechanical pressure effect on the developing fetus could be the implicating factor [14].

To our best knowledge, this is the first case to be reported with hemiscrotal agenesis and ipsilateral cryptorchidism associated with a perineal skin tag, unilateral monodactylous lower limb on the same side, unilateral cerebellar hypoplasia, and VSD. Interestingly, further genetic analysis is required to reach a final diagnosis. Unfortunately, advanced molecular diagnostic studies for this patient is not available in our country.