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Kabuki syndrome (KS) is characterized by typical facial features and patients are also affected by multiple congenital anomalies, of which congenital heart anomalies (CHAs) are present in 28.0 to 80.0%. In approximately 75.0% of patients, the genetic causes of KS are caused by mutation in the KMT2D gene. Although KS is a well-characterized syndrome, reaching the diagnosis in neonates is still challenging. Namely, newborns usually display mild facial features; therefore the diagnosis is mainly based on congenital malformations. In our case, a newborn was referred for next generation sequencing (NGS) testing due to the prenatally observed CHA. After birth, a ventricular septal defect (VSD), vesicoureteral reflux, muscular hypotonia, cleft palate, mild microcephaly, and some dysmorphic features, were noted. The NGS analysis was performed on the proband’s genomic DNA using the TruSight One Sequencing Panel, which enriches exons of 4813 genes with clinical relevance to the disease. After variant calling, NGS data analysis was predominantly focused on rare variants in genes involved in VSD, microcephaly, and muscular hypotonia; features observed predominantly in our proband. With the aforementioned protocol, we were able to determine the previously unreported de novo frameshift deletion in the KMT2D gene resulting in translation termination. Although our proband is a typical representative of KS, his diagnosis was reached only after NGS analysis. Our proband thus represents the importance of genotypephenotype driven NGS analysis in diagnosis of patients with congenital anomalies.

Congenital microcephaly (MCPH) is a neurodevelopmental disease associated to mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic knockouts we report here that, whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild microcephaly during development, lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs). Our novel mouse model of MCPH8 suggests that Cep135 deficiency results in centriole duplication, TP53 activation and cell death of NPs. Trp53 ablation in a Cep135-deficient background prevents cell death, but not microcephaly, and leads to subcortical heterotopias, a malformation seen in MCPH8 patients. These results suggest that microcephaly in some MCPH patients can arise from the lack of adaptation to centriole defects in NPs and may lead to architectural defects if chromosomally unstable cells are not eliminated during brain development.

This study analyzed possible associations between the trimester of maternal Zika virus infection (ZIKV) in pregnancy, severity of brain computed tomography (CT) findings and the presence of microcephaly at birth in children with Congenital Zika Syndrome (CZS). It was an analytical study in a cohort of children with CZS. Symptoms of maternal infection were dichotomized into the 1st trimester of pregnancy and other trimesters. Head circumference (HC) at birth was used to calculate the z-score. Mild microcephaly was defined as HC between 2 and ≥3 standard deviations (SD) below the mean for each gestational age and sex, and severe microcephaly when HC

ObjectiveHead circumference is considered a reliable assessment of the volume of the underlying brain. We sought to identify risk factors (maternal factors or antenatal antecedents) for microcephaly and to assess the effects of microcephaly on neonatal outcomes.DesignRetrospective cohort study.SettingData for all births in 2009-2017 were obtained from the Guangzhou Maternal-Fetal Care Database.ParticipantsAll singleton liveborn infants between 33 and 42 weeks’ gestation (n=45 663) were categorised using the Intergrowth-21st standard for microcephaly.Main outcome measuresPrevalence of mild, absolute and relative microcephaly at birth. We estimated associations of (1) maternal characteristics including Cantonese origin, parity, exposure to teratogens, TORCH infections (ie,Toxoplasmagondii, rubella virus, cytomegalovirus, herpes simplex virus), in vitro fertilisation conception, pre-eclampsia and maternal congenital anomalies with risk of each category of microcephaly, and (2) microcephaly with risk of in-hospital mortality and severe morbidity.ResultsA total of 2709 infants had a head circumference z-score >2 SD, resulting in an overall prevalence of microcephaly of 59.3 per 1000 infants, consisting of mild (54.1 per 1000), absolute (2.8 per 1000) and relative microcephaly (2.4 per 1000). In multiple logistic regression, absolute microcephaly was associated with in utero exposure to teratogens (OR 4.2, 95% CI 2.0 to 8.8) and TORCH agents (OR 3.2, 95% CI 1.1 to 9.5). Mild microcephaly was associated with Cantonese descent (OR) 1.5, 95% CI 1.3 to 1.7) and primiparity (OR 1.7, 95% CI 1.5 to 2.0). Absolute microcephaly was associated with a significantly higher odds of neonatal seizure (OR 8.7, 95% CI 1.1 to 69.1). Mild microcephaly was not associated with adverse neonatal outcomes overall.ConclusionsCantonese origin, exposure to teratogens, pre-eclampsia and TORCH infection may be risk factors for microcephaly. The high prevalence of relative microcephaly and associated poor outcomes suggests that high-risk women merit closer clinical management and follow-up to maximise fetal head development during pregnancy.

Rationale: Holoprosencephaly (HPE) is a severe congenital brain malformation resulting from failed or incomplete forebrain division in early pregnancy. Patient concerns: In this study, we reported a 9-month old infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst. Diagnoses: Potential genetic defects were screened directly using trio-case whole exome sequencing (WES) rather than traditional karyotype, microarray, and Sanger sequencing of select genes. Outcomes: A previous unpublished de novo missense mutation (c.1069C >G, p.H357D) in the 3rd zinc finger domain (ZFD3) of the ZIC2 gene was identified in the affected individual, but not in the parents. Sanger sequencing using specific primers verified the mutation. Extensive bioinformatics analysis confirmed the pathogenicity of this extremely rare mutation. Phenotype-genotype analysis revealed significant correlation between the 3rd zinc-finger domain with semilobor HPE. Lessons: These findings expanded the spectrum of the ZIC2 gene mutations and associated clinical manifestations, which is the first identification of a mutated ZIC2 gene in a Han infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst.

Introductory paragraphUntil recently missense germ-line mutations inACTB, encoding the ubiquitously expressed β-cytoplasmic actin (CYA), were exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF), a complex developmental disorder1,2. Here, we report six patients with previously undescribed heterozygous variants clustered in the 3’-coding region ofACTB. These patients present with clinical features different from BWCFF, including thrombocytopenia, microcephaly, and mild developmental disability. Patient derived cells are morphologically and functionally distinct from controls. Assessment of cytoskeletal constituents identified a discrete filament population altered in these cells, which comprises force generating and transmitting actin binding proteins (ABP) known to be associated with thrombocytopenia3–8.In silicomodelling and molecular dynamics (MD)-simulations support altered interactions between these ABP and mutant β-CYA. Our results describe a new clinical syndrome associated withACTBmutations with a distinct genotype-phenotype correlation, identify a cytoskeletal protein interaction network crucial for thrombopoiesis, and provide support for the hypomorphic nature of these actinopathy mutations.

Intellectual disability (ID) has an estimated prevalence of 1.5–2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.

THO/TREX (transcription/export) is a conserved eukaryotic complex that plays a crucial role in gene expression and prevents DNA damage during mitosis and meiosis. In mammals, TREX is essential during embryogenesis, determining stem cell fate specification by regulating posttranscriptional self-renewal and differentiation in several tissues. It is composed of a core called THO, consisting of THOC1, 2, 5, 6, 7, and additional proteins. Bi-allelic mutations in THOC6 have been associated to Beaulieu–Boycott–Innes syndrome (BBIS), a syndromic form of intellectual disability (ID). To date, nine patients harbouring homozygous or compound heterozygous mutations in THOC6 have been reported. Despite the clinical heterogenity and subtle dysmorphic features in some individuals, distinctive facial features are tall forehead, short and upslanting palpebral fissures, deep set eyes, flat philtrum, and malocclusion. Nonlife threatening congenital anomalies are common, including cardiac and renal malformations, anteriorly displaced anus, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis. Affected patients usually have short stature, mild microcephaly, and mild to moderate ID. Here, we describe an Italian patient with BBIS, carrying two compound heterozygous loss-of-function (LoF) variants in THOC6 (c.577C > T, p.R193* and c.792_793delCA, p.V264Vfs*48). In addition to the common phenotype, she displays cerebellar hypoplasia with severe vermian dysgenesis and hydrocephalus due to aqueductal stenosis, multiple skeletal anomalies and hypergonadotropic hypogonadism. Thus, we review the previous cases and discuss the phenotypic spectrum of BBIS, providing further evidence regarding the pivotal role of TREX complex in human development.

Alazami syndrome (AS) (MIM# 615071 ) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features.

In 1973, Jones and Smith described two maternal male first cousins with a similar pattern of malformation, including mental retardation, cubitus valgus, and unusual facies. The purpose of this report is to describe three additional cases, a 10-year-old male and his 30-year-old maternal uncle and an unrelated 15-year-old boy, bringing to five the total number of individuals with this disorder. The principal features include moderate mental retardation, mild microcephaly, a short philtrum, deep-set, downslanting palpebral fissures, multiple nevi, and striking cubitus valgus. Documentation of this disorder in two maternal male first cousins as well as in a male and his maternal uncle support an X-linked recessive mode of inheritance for this condition.

Anterior cervical hypertrichosis (ACH) is a rare form of localized hypertrichosis with 15 previously reported cases. ACH has been considered to be a dominant phenotype, either X-linked or autosomal [OMIM 600457]. ACH was associated with hereditary motor and sensory neuropathy (HMSN) in one family, in which the proband also exhibited severe chorioretinal degeneration and optic atrophy, probably as a different entity [OMIM 239840]. A Mexican boy with congenital ACH associated with moderate mental retardation, abnormal EEG, mild microcephaly, hypertrichosis on the back, and hallux valgus is presented here. An equal sex ratio found in 16 reported cases as well as the suggestion of a paternal age effect in one report appear most consistent with an autosomal dominant mode of inheritance for this trait. It remains unclear if isolated ACH, ACH-HMSN, or other associated findings reported in patients with ACH, including unusual features found in our case, are part of ACH or fortuitous associations, due to the small number of affected patients and different ascertainment biases present in previous reports.

We report a case of an unbalanced cryptic telomeric translocation 46,XY,der(17),t(9;17)(q34.3;p13.3) in a boy with dysmorphic features and developmental delay. The proband had intrauterine growth retardation, postnatal short stature, and mild microcephaly. Magnetic resonance imaging showed incomplete myelination, but no evidence of lissencephaly. Cytogenetic analysis of the proband's peripheral blood showed an abnormal 17p. Fluorescence in situ hybridisation (FISH) with a Miller-Dieker cosmid probe did not detect a deletion for that area. Further analysis with a 17p telomere specific probe identified an unbalanced telomeric translocation. The same probe was used to determine the presence of an apparent balanced translocation t(9;17)(q34.3;p13.3) in the mother of the proband. The balanced translocation was confirmed with two cosmids that map distally on 9q34.3. Two phenotypically normal half sibs, a maternal aunt, a maternal uncle, and the maternal grandmother were found to be balanced translocation carriers as well. A subtle translocation carriers as well. A subtle translocation is one mechanism that can produce an abnormal phenotype in a patient who had a normal karyotype at lower band resolution levels.

A 7-year-old boy with 49,XXYYY karyotype is reported. Physical examination revealed facial dysmorphism, mild microcephaly, limitation of supination at the elbows, delayed bone age and moderate mental retardation.

Mutations in ASPM (abnormal spindle-like microcephaly associated) cause primary microcephaly in humans, a disorder characterized by a major reduction in brain size in the apparent absence of nonneurological anomalies. The function of the Aspm protein in neural progenitor cell expansion, as well as its localization to the mitotic spindle and midbody, suggest that it regulates brain development by a cell division-related mechanism. Furthermore, evidence that positive selection affected ASPM during primate evolution has led to suggestions that such a function changed during primate evolution. Here, we report that in Aspm mutant mice, truncated Aspm proteins similar to those causing microcephaly in humans fail to localize to the midbody during M-phase and cause mild microcephaly. A human ASPM transgene rescues this phenotype but, interestingly, does not cause a gain of function. Strikingly, truncated Aspm proteins also cause a massive loss of germ cells, resulting in a severe reduction in testis and ovary size accompanied by reduced fertility. These germline effects, too, are fully rescued by the human ASPM transgene, indicating that ASPM is functionally similar in mice and humans. Our findings broaden the spectrum of phenotypic effects of ASPM mutations and raise the possibility that positive selection of ASPM during primate evolution reflects its function in the germline.

We report on a 7 years and 4 months old Greek boy with mild microcephaly and dysmorphic facial features. He was a sociable child with maxillary hypoplasia, epicanthal folds, upslanting palpebral fissures with long eyelashes, and hypertelorism. His ears were prominent and dysmorphic, he had a long philtrum and a high arched palate. His weight was 17 kg (25th percentile) and his height 120 cm (50th percentile). High resolution chromosome analysis identified in 50% of the cells a normal male karyotype, and in 50% of the cells one chromosome 18 showed a terminal deletion from 18q21.32. Molecular cytogenetic investigation confirmed a del(18)(q21.32-qter) in the one chromosome 18, but furthermore revealed the presence of a duplication in q21.2 in the other chromosome 18. The case is discussed concerning comparable previously reported cases and the possible mechanisms of formation.

Very little is known about the molecular basis of autosomal recessive MR (ARMR) because in developed countries, small family sizes preclude mapping and identification of the relevant gene defects. We therefore chose to investigate genetic causes of ARMR in large consanguineous Iranian families. This study reports on a family with six mentally retarded members. Array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH) revealed a deletion of approximately 150-200 kb, encompassing the promoter and the first six exons of the MCPH1 gene, one out of four genes that have been previously implicated in ARMR with microcephaly. Reexamination of affected individuals revealed a high proportion of prematurely condensed chromosomes, which is a hallmark of this condition, but in spite of the severity of the mutation, all patients showed only borderline to mild microcephaly. Therefore the phenotypic spectrum of MCPH1 mutations may be wider than previously assumed, with ARMR being the only consistent clinical finding.

PURPOSE: To report a case of cerebroocular myopathy syndrome with a focal absence of the Descemet membrane. DESIGN: Clinicopathological case report. METHODS: A clinical and histopathologic examination of eye, brain, and viscera of a white male newborn of normal term, who died at 11 days of age with the diagnosis of cerebroocular myopathy syndrome. RESULTS: The autopsy revealed hazy left cornea, hypoplasia of the cerebellum, and corpus collusum with mild microcephaly. Microscopy of the left eye showed the additional findings of a central focal defect of the Descemet membrane with an absence of the posterior third of central corneal stroma and delicate fibrous strands connected to the iris. CONCLUSION: The absence of the Descemet membrane and the missing posterior corneal keratocytes as well as the fibrous strands connecting the iris are findings to be added to the previously reported signs of cerebro-ocular myopathy.

Duplication of chromosome 19, partial or complete, has rarely been described. Trisomy of its short arm (19p) was briefly reported in abstract form by Byrne et al 1 in 1980 in a newborn patient with dysmorphism and intrauterine growth retardation and in 1992 by Salbert et al 2 in a dysmorphic newborn male. The delineation of these two patients was hampered by deletion of the terminal band of chromosome 13 in the first case and partial deletion of distal chromosome 3q in the second case. The infant presented here is the first and only child of non-consanguineous parents. The family history is unremarkable apart from epilepsy in the maternal grandmother. The pregnancy was uneventful with no intrauterine growth retardation. The mother and the father were aged 28 and 35 years at the time of birth. He was born at 41 weeks of gestation by spontaneous delivery. He sat alone at 6 months, walked at 17 months, and …

A family comprising mother, father, and five children is described. Four of the children were found to excrete massive amounts of D(+)-glyceric acid in their urine. This was verified by gas chromatography-mass spectrometry and the configuration determined by capillary gas chromatography of O-acetylated menthyl esters. The excretion ranged from 10.8 to 19.9 mmol/24 h. The remaining child and the parents showed no evidence of this unusual metabolite. The virtual absence of clinical manifestations in this family was particularly interesting. Only two of the children showed any clinical abnormality and this was limited to mild microcephaly and speech delay; the other two children found to excrete large amounts of D(+)-glycerate were healthy and developmentally normal at 7 y and 9 y of age. There was a marked increase in the excretion rate of D(+)-glycerate in response to both oral fructose and serine loading. These results are consistent with a deficiency of D(+)-glycerate kinase and indicate the potentially benign nature of this disorder.

Evaluation of 19 patients with the Williams elfin facies syndrome, in order to more completely delineate the total spectrum of the disorder, indicates that "infantile hypercalcemia, peculiar facies, supravalvular aortic stenosis" designation which was heretofore used is inappropriate. Only 32% of the patients have evidence of supravalvular aortic stenosis and not one of them has had documented hypercalcemia, including eight patients who had a serum calcium determination in the first year of life. Rather, the most consistent features are growth deficiency which is predominantly of postnatal onset, mild microcephaly with mental deficiency, and an altered pattern of facial development which includes short palpebral fissures, a stellate pattern in the iris, medial eyebrow flare, a depressed nasal bridge with anteverted nares, and thick lips. The disorder is a sporadic occurrence of unknown etiology.

THE Williams syndrome is characterized by the triad supravalvular aortic stenosis, mental retardation, and an elfin facies.1 , 2 In addition, mild microcephaly, neurologic dysfunction, hallux valgus, hernias, pectus excavatum, and other congenital cardiac and vascular defects may be present. The unique facies is characterized by a medial eyebrow flare, short palpebral fissures, ocular hypotelorism, a depressed nasal bridge, periorbital fullness, strabismus, blue eyes, a stellate pattern in the iris, prominent lips, and molar hyperplasia.2 The syndrome is often associated with idiopathic hypercalcemia of infancy, which usually occurs in the first year of life.3 4 5 6 7 8 9 10 11 Patients have increased sensitivity to vitamin D.5 , 6 Balance . . .

Two cases with association of Hirschsprung disease and preaxial polydactyly occurring in siblings were reported. The proband was a female infant examined on the 12th day after birth. Major findings were as follows: growth retardation, mild microcephaly, rightanophthalmia, left exophthalmus associated with double disk and coloboma choroidae, ocular hypotelorism, cleft lip and palate, and bilateral preaxial polydactyly. CT scan of the brain revealed agenesis of the corpus callosum and atrophy of the cerebral cortex. Autopsy revealed alobar holoprosencephaly and agenesis of the corpus callosum, right optic nerve and olfactory nerve. Aganglionosis of the rectumwas noted at a site 10 cm from the anus. When her brother was born, bilateral preaxial polydactyly was found. He had Hirschsprung disease as well.

A female with the orocraniodigital (Juberg-Hayward) syndrome is described in whom, in addition to bilateral cleft lip and palate, mild microcephaly, and anomalous thumbs and toes, there was absence of the pituitary fossa and a more widespread skeletal dysplasia.

Trigonocephaly was found in six relatives through three generations of one family. The propositus was ascertained at birth because of omphalocele. In addition to trigonocephaly, he had minor ear, vertebral, and genital abnormalities. His father had mild microcephaly, and both had minor eye abnormalities. None of the other four affected individuals had any other malformations. In this family, trigonocephaly is an autosomal dominant trait. The ratio of affected males to affected females was 5 to 1, and although the paucity of affected females is not statistically significant, we speculate that it may reflect variable expressivity or sex limitation of the trait. We conclude that the condition in this family represents a unique syndrome in which trigonocephaly is not associated with functional brain abnormalities and where craniosynostosis is limited to the metopic region.

Four cases of variant hyperphenylalaninaemia during pregnancy are presented. Babies born to mothers with blood phenylalanine concentrations of 4-8 mg/dl were normal and did not exhibit significant microcephaly, although one did have a major congenital anomaly (exstrophy of the bladder). The mother with blood phenylalanine concentrations of 6-12 mg/dl during pregnancy delivered three of four infants with mild microcephaly but normal intellectual function. The data suggest that phenylalanine concentrations of 4-8 mg/dl are reasonable and desirable during pregnancy in hyperphenylalaninaemic women. Furthermore, the data do not support or refute the justification hypothesis of Bessman et al.

We report on a 10-year-old boy with short stature, mild microcephaly, malar hypoplasia, highly arched palate, prominent upper incisors, micrognathia, and unusual digital anomalies involving the proximal phalanges of fingers 2-5 of both hands. To our knowledge, this is a hitherto undescribed syndrome.

Background A syndrome of young-onset diabetes mellitus associated with microcephaly, epilepsy and intellectual disability caused by mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene has recently been described. Case report We report two siblings from the fourth family reported to have diabetes mellitus as a result of a TRMT10A mutation. A homozygous nonsense mutation p.Glu27Ter in TRMT10A was identified using targeted next-generation sequencing and confirmed by PCR/Sanger sequencing. Diabetes was diagnosed while the subjects were in their 20s and was characterized by insulin resistance. Epilepsy and intellectual disability were features in common. Mild microcephaly was present at birth but their final head circumferences were normal. Conclusion Our report provides independent confirmation of the role of TRMT10A mutations in this syndrome and expands its phenotypic description. TRMT10A sequencing should be considered in children or adults with young-onset diabetes who have a history of intellectual disability, microcephaly and epilepsy. This report also shows the advantages of using a targeted panel to identify previously unsuspected monogenic diabetes among young-onset non-insulin-dependent diabetes in the absence of obesity and autoimmunity.

IN our human gene localization studies we have sought abnormal inheritance patterns of qualitative gene markers and have evaluated possible gene dose effects through quantitative enzyme assays in patients with abnormal chromosome constitutions. During these studies a patient with the cat cry syndrome was found to have a half normal value for red blood cell triosephosphate isomerase (EC 5.3.1.1). Clinical features which suggest that the patient has the cat cry syndrome include mental and physical retardation, a weak plaintive cry, moon facies, mild microcephaly, epicanthal folds, antimongoloid slant to the palpebral fissures and hypertelorism1.

Four unrelated examples of partial deletion of the long arm of chromosome No. 18 have been briefly reported by us (Lancet ii: 641 [1966]). These patients have now been studied in detail. The typical features of this syndrome are mental retardation, short stature, impaired hearing with atretic or narrow ear canals, prominent antihelix, mild microcephaly, typical facies manifested by prominent forehead—perioral areas and deep set eyes, proximal implantation of the thumbs, increased number of whorl fingerprint patterns, hypotonia, vertical tali, fundoscopic anomalies and asymptomatic congenital heart anomalies. Relatives of three of the patients had normal chromosomes. The father and two siblings of the fourth patient had one metacentric No. 18, interpreted as a pericentric inversion. The deletion in this last patient probably arose by a crossover in the father between the metacentric and the normal No. 18 (‘aneusomy by recombination’). These four patients represent partial monosomy No. 18 but nonetheless the findings are not obviously the antithesis of the trisomy 18 syndrome. The retardation and morbidity associated with this chromosome disorder are less severe than those found with the usual autosomal trisomies. Since survival does not seem to be affected by this disorder, these patients will likely be found among older children. (SPR)

To the Editor:— The picture on the cover of the Feb 28 issue ofThe Journal"Le Pied-Bot" interests me, as one who has specialized in cerebral palsy. I have long contended that this child did not represent a classical clubfoot, but illustrated more a right hemiplegia, in which the internal rotators and flexors were more spastic than the external rotators and extensors. Although I use the word "spastic," this could be a tension athetoid hemiplegia. The factors favoring the hemiplegia include the facial asymmetry and the tooth markings so frequently seen in the patient with congenital cerebral palsy. Although the child's expression is one of cheerfulness, it is not necessarily one of intelligence. There is a possibility of a mild microcephaly; certainly the frontal lobes are not large. The most compelling feature of all is the fashion in which he carries his right upper extremity, internally rotated, dropped at