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PURPOSE Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy (DEE) with early-onset seizures and severe intellectual disability. METHODS By international collaboration we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders (NDDs). By western blotting we investigated the consequences of missense variants in vitro. RESULTS In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe DEE in 16 individuals. We now identified also de novo missense variants in the GTPase domain in six individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences.Furthermore, we observed bi-allelic splice-site and truncating variants in nine families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION By identifying phenotype-genotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying bi-allelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2 related disorders including both autosomal dominant and recessive NDDs.

Whole-arm translocations are relatively rare among hematological malignancies. There are a few reports on der(18;21)(q10;q10). This is a recurrent but rare abnormality. Only about 11 cases harboring der(18;21)(q10;q10) have been reported. However, combined der(18;21) (q10;q10) and gain of chromosome 21 is even rarer, with only three cases reported. The previous cases were with AML, AML-M2, and aCML diagnosis. We report the first case of Ph-like, B-lymphoblastic leukemia (B-ALL) with +21 and der(18;21)(q10;q10) which resulted in loss of 18p and a gain of 21q. We address tumorigenesis and morphological characteristics of hematological malignancies involving der(18;21)(q10;q10), along with a review of the literature.

A case is presented in which apparent non-mosaic trisomy 16 was found in chorionic villi (direct and culture) obtained from a patient undergoing first-trimester prenatal diagnosis. The fetal karyotype subsequently was determined to be 46,XX by follow-up amniocentesis. Serial ultrasonographic examinations revealed placental sonolucencies and intrauterine growth retardation. At 37 weeks, a small-for-gestational-age female was delivered by Caesarean section for fetal distress. Postnatal cytogenetic studies revealed a normal female karyotype in cord blood and mosaic trisomy 16 in placental tissues. These findings suggest that in cases where aneuploidy is confined to placental tissues, it may have biological significance, as evidenced by the apparent placental dysfunction and poor fetal growth in this case.

We present a family who sought prenatal diagnosis in order to bear a healthy child to serve as an HLA-identical bone marrow donor for their son affected with Wiskott-Aldrich syndrome. They intended to abort HLA-incompatible fetuses who would have been unsuitable bone marrow donors. This case led us to conclude that prenatal diagnosis should not be used to benefit a third party or facilitate the conception or abortion of a fetus for the purpose of generating an organ for transplantation. The limits of parental autonomy and physician responsibility are discussed.

Setleis syndrome, an autosomal recessive disorder characterized by "coarse" face, temporal cutis aplasia, double upper eyelashes, absent lower eyelashes, chronic conjunctivitis, and prominent thick lips, was reported previously in 8 Puerto Rican children. We report on 3 unrelated children (one mentally retarded) with Setleis syndrome who are not of Puerto Rican descent. Two of our patients had imperforate anus, which has not previously been reported. The evolution of the phenotype over time is illustrated.

We report on 11 new cases of Proteus syndrome to illustrate the broad range of the phenotype in this hamartomatous dysplasia. The cardinal manifestations of this sporadic disorder are hemihypertrophy, macrodactyly, exostoses, scoliosis, cavernous hemangiomas, lipomas, linear sebaceous nevi, and deeply rugated soles of the feet. Intelligence is usually normal. The differential diagnosis includes Klippel-Trenaunay-Weber and partial lipodystrophy syndromes.

We report on a newborn boy with manifestations of Fryns syndrome who also had a mosaic tandem duplication of chromosome 1q24-31.2. The child had a diaphragmatic hernia, cleft palate, hypoplastic and absent digits, micrognathia, long philtrum, thin upper lip, and anteverted nose. The baby died at age 5 hours. An autopsy demonstrated absent right middle lobe of the lung, bilateral renal cysts, hypoplastic renal arteries, urethral stricture, hydronephrosis, and aortic coarctation. The brain was abnormal with absent olfactory tracts and cerebral and cerebellar heterotopias. This is the first report of a chromosome anomaly in a child with Fryns phenotype. It suggests that the gene for Fryns syndrome may be located in the region 1q24-31.2.