Male Rett syndrome variant: application of diagnostic criteria

Abstract

Classic Rett syndrome (RS) has been described in females only. Although an X chromosome origin is probable, it has not been substantiated. It is possible, therefore, that RS could occur in males. The authors describe a male with RS and review all the reported cases involving male patients. The authors compare their patient to the other patients and examine the applicability of the classic RS diagnostic criteria to this variant. To date, nine male patients with RS have been reported. The authors describe an additional male who met seven of nine necessary criteria and six of eight supportive criteria as defined by the RS Diagnostic Criteria Work Group. When the authors applied these criteria to the other nine reported patients, many necessary inclusion criteria were not met despite the absence of exclusion criteria. The supportive criteria were even more variable and limited in many patients. In conclusion, males with RS appear to represent a heterogeneous phenotype, with clinical features that may meet many but not all of the necessary diagnostic criteria of classic RS. Less restrictive criteria are needed to include this variant, which should be considered when evaluating males with idiopathic developmental regression, autistic features, and loss of hand function.

Introduction

In 1966, Rett [1] described a unique disorder characterized by global deceleration of psychomotor development and subsequent loss of acquired cognitive and motor skills. The first full description of Rett syndrome (RS) in the literature was reported by Hagberg et al. [2] in 1983. Classic RS has been found in females only. The syndrome has its onset toward the end of the first year of age or during the first half of the second year and is associated with a slowly progressive course. Subsequently, several RS variants have been described and the syndrome appears to represent a more heterogeneous phenotype than was first realized [3].

In 1983, Hagberg et al. [2] first suggested that RS is the result of a dominant mutation on the X chromosome that results in the early deaths of male fetuses. However, no evidence for either excessive fetal loss or a deficiency of males in RS families, such as would be expected if this hypothesis was correct has been found [4]. Extensive research has failed to identify a genetic marker for RS. Migeon et al. [4] concluded from the current data that no compelling evidence supports the proposed explanations for sex-limited expression in RS.

In 1988 the Rett Syndrome Diagnostic Criteria Work Group [5] proposed revised criteria that did not restrict the syndrome to females. A more recent model for the clinical delineation of atypical cases of RS includes the male variant as a separate subtype [6].

To date, nine male patients with RS have been reported [3], [7], [8], [9], [10], [11], [12]. The authors describe an additional patient and review the literature on the other nine reported patients. The authors also examine the applicability of the classic RS diagnostic criteria to this variant.