Chudley-Rozdilsky syndrome (CRS) is a very rare multisystem disease. The only two patients ever described suffered from a congenital non-progressive myopathy of type multiminicore myopathy, severe mental retardation, short stature and facial anomalies, hypoplasia of the pituitary fossa and pituitary gland as well as hypogonadotropic hypogonadism resulting therefrom. Little is known about the etiology and pathogenesis of the disease. Treatment can only be supportive until new insights are gained.
CRS has been described as a "complex dysmorphic syndrome" [1], but otherwise all data available stem from the single case report published by Chudley et al. in 1985 [2]. Non-progressive myopathy and intellectual disability are the hallmarks of CRS and are rarely observed concomitantly in other entities. The former manifests in form of facial and generalized weakness, bilateral ptosis, partial gaze palsy, and severe lumbar lordosis, and those are mostly present at birth. Indeed, neonates are hypotonic, so-called "floppy infants". Severe mental and growth retardation becomes apparent when the child fails to reach the corresponding developmental milestones. A child experiencing CRS may only grow to a short stature. Additional symptoms of CRS are borderline microcephaly, characteristic facial features - particularly anteverted ears, hypertelorism, antimongoloid palpebral slants, exotropia, a prominent nasal bridge, and a highly arched palate -, and hypogonadism. Secondary sex characteristics are hardly developed. One of the patients described by Chudley and colleagues was myopic and both had bilateral clinodactyly.
The non-progressive myopathy presented by CRS patients has been classified as multiminicore myopathy. In the 1980s, the diagnosis of this condition was based on the histological examination of tissue samples obtained by means of muscle biopsies. In detail, Chudley and colleagues observed a moderate variation of fiber diameters, numerous internally placed nuclei in about half of all fibers, atrophic type 1 muscle fibers, focal loss of cross striations and cores of myofibrillar disruption. Those cores were located eccentrically and perpendicular to the long axis of the muscle fiber. They were largely missing mitochondria. Neither necrotic foci nor infiltration of inflammatory cells have been noted. Affected muscle fibers didn't seem to regenerate and were neither replaced by fibrous tissue. Apparently healthy and degraded shares of the muscle fiber were separated by a well defined border [2].
Biochemical analyses and diagnostic imaging may be employed to confirm hypogonadotropic hypogonadism and to determine the state of skeletal development. Blood counts yield normal results, but serum concentrations of gonadotropins, testosterone and estradiol in men and women, respectively, are below reference ranges. A generalized retardation in skeletal maturation has been observed in both patients. Growth plate fusion is significantly delayed. Also worth mentioning are the typically small cranial vault and pituitary fossa [2].
Molecular biological studies are highly recommended in case of suspected CRS to fill existing knowledge gaps regarding the etiology of the disease. While gene panel sequencing may be a good starting point, a more comprehensive approach would be required to identify possible sequence anomalies that have not been yet related to congenital myopathy, mental retardation and combinations thereof [3]. Whole-exome sequencing is likely to yield interesting results and is less cost-intensiv than whole-genome sequencing [3].
Causal treatment is not available. Patients could most likely benefit from a tailor-made, multidisciplinary approach to therapy that comprises regular physiotherapy, the provision of orthopedic devices, hormone replacement therapy, and dietary supplementation. Surgical interventions may be considered.
Due to their severe intellectual disability, CRS patients require the attention of professionals in alternative educational institutions [4]. Also, parents and possibly other family members should receive psychological support.
Even though motor impairments, skeletal anomalies and mental retardation as well as additional symptoms reduce life quality, CRS patients have been shown to live well into adulthood [2]. Little can be stated at present regarding their overall life expectancy, but life-threatening complications of the disease have not been described. It is remarkable that CRS patients don't seem to experience significant respiratory muscle weakness, while those suffering from typical multiminicore myopathy often do [1].
Both patients known to have suffered from CRS, a man and a woman, were children of a cousins, i.e., of third-degree relatives. Neither parent showed any symptoms of CRS. This also applies to four siblings of the affected individuals, although one of them and a distant relative proved to be intellectually disabled [2]. These facts argue in favor of an autosomal recessive inheritance pattern. Possibly, sequence anomalies as those observed in multiminicore myopathy may have accounted for the disease. A multigenic origin of CRS may also be presumed, but appears less likely due to the high phenotypic consistency between both patients and the near-total absence of CRS-related symptoms in their siblings. In the end, the current state of knowledge does not allow for any reliable statements to this end.
Only a single case report of CRS has ever been published [2]. This syndrome is one of the few conditions in which congenital myopathies are not restricted to the skeletal muscle [4]. Other conditions pertaining to that group comprise very rare forms of Nemaline myopathy with central nervous system involvement [5] as well as the combination of "microcephaly, mental retardation, spasticity with hyperreflexia, cerebellar dysfunction, short stature, Hirschsprung's disease, pharyngeal web, and facial dysmorphism" described in a case report by Kim et al. [6].
While the overall prevalence of congenital myopathies has been estimated to 1 in 26,000 people in the United States [7] and to 1 in 50,000 individuals aged over five years in Denmark [8], the prevalence of multiminicore myopathy is presumed to be much lower. Most commonly, multiminicore myopathy results from mutations in the gene encoding for the skeletal muscle ryanodine receptor [9]. Regarding those mutations, a heterozygous mutation carrier frequency of 1 in 2,000 persons has been determined in the Japanese population [10]. Thus, the likelihood of both parents of a child being such carriers is as low as 1 in 4,000,000. The prevalence of CRS can only be described as anectodically [4].
The patients described by Chudley et al. were brother and sister [2]. Thus, it can be concluded that CRS may affect people of both genders.
Virtually nothing is known about the etiology of the disease and thus, the pathophysiological events leading to the complex clinical picture remain elusive.
Affected families might benefit from genetic counseling if the identification of the causal mutation was achieved. Precise knowledge regarding the etiology of the disease would also allow for an early diagnosis during pregnancy. Considering what is known to date about CRS, a prenatal diagnosis seems highly unlikely: Growth retardation is not to be expected in utero, leaving reduced fetal movements as the only, yet unspecific clue towards the disease [11].
In 1985, Chudley and colleagues published a case report titled "Multicore disease in sibs with severe mental retardation, short stature, facial anomalies, hypoplasia of the pituitary fossa, and hypogonadotrophic hypogonadism" [2]. This presumably genetic disorder hadn't been described before and has subsequently been named CRS.
The affected siblings were children of a consanguineous couple and suffered from a congenital, non-progressive myopathy associated with generalized weakness that has been diagnosed as multicore myopathy after the affected individuals reached adulthood [2]. Today, the term multiminicore myopathy is preferred over the term of multicore myopathy, and while this type of myopathy is known to be inherited in an autosomal recessive manner, it is not usually associated with neurological and endocrinological disorders as those described by Chudley et al. Multiminicore myopathy has repeatedly been related to central core myopathy and malignant hyperthermia, though [11] [12]. It may result from mutations in the genes encoding for the skeletal muscle ryanodine receptor (RYR1) or for selenoprotein N (SELN).
As can be inferred from the title given above, CRS encompasses mental retardation and developmental disturbances affecting the pituitary fossa and the pituitary gland, which lead to hypogonadotrophic hypogonadism, then still named "sexual infantilism". Although Chudley and colleagues carried out cytogenetic studies, they found little more than a few disperse anomalies whose accumulation was probably due to consanguineous relationships within the family. No chromosomal aberration could clearly be related to the observed phenotype [2]. To date, the genetic cause of CRS remains unclear. Although it may be speculated that CRS results from SELN or RYR1 mutations combined with mutations in other genes, this hypothesis cannot currently be proven or refuted.
Chudley-Rozdilsky syndrome (CRS) is a very rare disease that has only been described in two patients, one boy and one girl. In detail, Chudley, Rozdilsky and their colleagues published a case report about two siblings suffering from a non-progressive myopathy, severe mental retardation, short stature and facial anomalies, skeletal defects and an impaired sexual development. Both were born as floppy infants, i.e., they presented with marked muscle hypotonia at birth. Furthermore, those neonates showed unusual facial features, namely widely divergent eyes with slanting palpebral fissures, drooping upper eyelids, a prominent nasal bridge, and a highly arched palate. During early development, severe mental and growth retardation became apparent. Both grew to a final height of 140-150 cm and achieved an IQ of approximately 20. They also suffered from severe lordosis, an abnormal curvature of the spine. Even after adolescence, their genitals remained childlike, and they hardly developed secondary sex characteristics such as axillary and pubic hair, and breast growth in the female patient.
At the time of diagnosis, the patients were 25 and 38 years old. Nothing indicated they had a shorter-than-normal life expectancy, but the subsequent evolution of their disease has not been made public. The origin of CRS remain unknown, although it seems likely the disease is inherited in an autosomal recessive manner. Children of consanguineous couples are thus more likely to experience CRS. Due to significant knowledge gaps regarding the causes of the disease, treatment can and was mainly supportive. Affected individuals could benefit from regular physiotherapy, the provision of orthopedic devices, hormone replacement therapy, and dietary supplementation, their families from psychological support.