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Eight patients in three families had mental retardation, characteristic facies and hands, and skeletal changes;the clinical features suggested to us that they had a syndrome previously thought to represent two entities described by Lowry and associates 1 and by Coffin and associates, 2 respectively. New findings include skeletal, orodental, and dermatoglyphic abnormalities and histopathologic changes suggesting that the syndrome is a heritable disorder of connective tissue. Severe expression in males and transmission through mildly affected females suggest X-linked or sex-influenced autosomal dominant inheritance.

Two brothers with Coffin syndrome are presented and the fifteen other cases available in the literature are reviewed. The molecular defect causing this clinically recognizable syndrome is unknown, and the mode of inheritance may be a sex-linked recessive, but a sex-limited autosomal dominant or autosomal dominant with variable degree of expression cannot be fully excluded at the present time.

Coffin–Lowry Syndrome (CLS) is an X-linked genetic disorder associated with cognitive and behavioural impairments. CLS patients present with loss-of-function mutations in the RPS6KA3 gene encoding the mitogen-activated protein kinase (MAPK)–activated kinase p90 ribosomal S6 kinase 2 (Rsk2). Although Rsk2 is expressed in the embryonic brain, its function remains largely uncharacterized. To this end, we isolated murine cortical precursors at embryonic day 12 (E12), a timepoint when neuronal differentiation is initiated, and knocked-down Rsk2 expression levels using shRNA. We performed similar experiments in vivo using in utero electroporations to express shRNA against Rsk2. Rsk2 knockdown resulted in a significant decrease in neurogenesis and an increase in the proportion of proliferating Pax6-positive radial precursor cells, indicating that Rsk2 is essential for cortical radial precursors to differentiate into neurons. In contrast, reducing Rsk2 levels in vitro or in vivo had no effect on the generation of astrocytes. Thus, Rsk2 loss-of-function, as seen in CLS, perturbs the differentiation of neural precursors into neurons, and maintains them instead as proliferating radial precursor cells, a defect that may underlie the cognitive dysfunction seen in CLS.

The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1(ob)(-/-) mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1(ob)(-/-) mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1(ob)(-/-) mice without affecting other organ weight, while a high-protein diet overcame Atf4(-/-) and Rsk2(-/-) mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.

A family is reported in which the mother and 4 of her 6 children are affected by a constellation of abnormalities including mental handicap, abnormal facies, short stature, soft fleshy hands with sapering fingers and skeletal abnormalities. The family is believed to represent a further group of individuals with Coffin-Lowry syndrome. Additionally, one affected daughter has symptoms suggestive of schizophrenia and one affected son has severe sensorineural deafness.

Two unrelated patients with Coffin-Lowry syndrome are described. The main characteristics of a typical face, thick hands with tapering fingers and a transverse hypothenar crease, general hypotonia with extensible joints made diagnosis possible before the age of 6 months. A persistent large anterior fontanel beyond the age of two years may be another associated finding. Retarded bone age, coarsity of the face and skeletal malformations considered characteristic in adult patients were not present. Early recognition of Coffin-Lowry syndrome is important for genetic counseling and prevention of severe skeletal malformations.

The Coffin-Lowry syndrome is an established syndrome of mental retardation, a characteristic facies and skeletal anomalies. This paper describes 12 cases from eight families and compares their findings with those of previously reported patients. The differential diagnosis is considered. Physical findings and pedigree data strongly support X-linked semi-dominant inheritance. The gene appears widely distributed and, as expected, a significant proportion of cases represent new mutations. We cannot confirm the metacarpal-phalangeal profile or fingertip dermatoglyphics as useful diagnostic aids. Skin biopsy studies from four of our patients gave no evidence for a primary disorder of lysosomes or a degenerative disease. Caution is urged before assuming that such patients will all show intellectual deterioration.

We revisited a family with the Coffin-Lowry syndrome (CLS) first reported by Procopis and Turner in 1972. Twelve affected members are now known in 3 generations of which 9 were seen personally. DNA marker studies supported X-linkage with localization of CLS to Xp near DXS43 at p22.2-22.1 (theta = 0.001 Z = 2.71). Such linkage is reinforced by positive lod scores for DXS28 (theta = 0.00, Z = 0.90) and for DXS84 (theta = 0.09, Z = 1.56). Recombination with DXS84 and DXS164 places CLS distal to DMD in Xp21-pter.

We describe the major autopsy findings in two adult sibs of the original pedigree of Lowry et al [Am J Dis Child 121:496-500, 1971]. These results support the idea that Coffin-Lowry syndrome is a systemic connective tissue disorder. Visceral neuropathy was also noted as the basis of extensive intestinal diverticular disease.

Two adult, mentally retarded males with the typical features of the Coffin-Lowry syndrome are reported. Further family investigation led to the same diagnosis in a 2.5-year-old male cousin, and to the identification of five female carriers, with variable clinical expression of this X-linked inherited mental retardation syndrome.

The Coffin-Lowry syndrome (McKusick No. 30360) is a rare genetically transmitted disorder characterized by severe mental retardation, "coarse" facial appearance, thick soft skin, tapering fingers, and progressive skeletal abnormalities. X-linked inheritance is implied since the males are severely affected with variably mild manifestations in carrier women. We have performed a linkage analysis with many X-linked RFLP markers in 4 families. Positive two-point lod scores were obtained with DXS28 (z(theta) = 2.00 at theta = 0.05) and DXS41 (z(theta) = 1.26 at theta = 0.10). We performed a 5-point linkage analysis using the LINKMAP program assuming that DXS16 and DXS43 are a single locus and using the following fixed map (distances in centimorgans): DXS85 - 18cM - (DXS16, DXS43) - 13cM - DXS41 - 5cM -DXS28. This gave a multipoint lod score of 3.41 for a localisation in Xp22.2-p22.1, between DXS43 and DXS41.

MIYAZAKI, K., YAMANAKA, T. and OOHIRA, A. Enhanced Accumulation of Hyaluronate in the Culture of Skin Fibroblasts from Two Patients with Coffin- Lowry Syndrome. Tohoku J. Exp. Med., 1989, 158 (4), 325-334-Cultured skin fibroblasts were prepared from two unrelated adult patients with full expressions of Coffin-Lowry syndrome. Glycosaminoglycans (GAGs) were isolated either from the medium or from the cell layer of cultured skin fibroblasts. Two-dimensional electrophoresis of GAG preparations on cellulose acetate film revaled that hyaluronate was the major component both in the medium and in the cell layer. Quantitative analysis of GAGs was carried out by measuring optical density at 615nm of Alcian blue-stained GAG spots on electrophoretograms. Increase in the hyaluronate content was found both in the culture medium and in the cell layer of Coffin-Lowry fibroblasts. In addition, the incorporation of [14C]glucosamine into hyaluronate was similarly activated in skin fibroblasts from patients, suggesting the active biosynthesis and/or the suppressed degradation of hyaluronate by cultured skin fibroblasts from Coffin-Lowry syndrome. The abnormal metabolism of hyaluronate in Coffin-Lowry fibroblasts may be implicated in some of the clinical aspects of this genetic disorder.

An epidemiological study was carried out on the group of moderately retarded brothers (IQ, 30-55) identified by Turner and Turner [1974]. Of the original 58 sets of brothers, 54 sets (now 17 to 32 years old) were traced; another four sets (missed in the earlier survey) were added. Forty-five of the 58 pairs were diagnosed as having nonspecific X-linked mental retardation (MR) giving an overall frequency of 5.57 moderately retarded males/10,000 male births. In 12 of the 45 families, affected males had the fragile(X) and macroorchidism; six had macroorchidism alone, giving a frequency of 2.8 moderately retarded males with X-linked MR and macroorchidism +/- the fragile(X) per 10,000 males. Corresponding heterozygote frequencies are 7.34 and 3.65/10,000 females respectively. A new subgrouping of nonspecific X-linked mental retardation is described in six families: X-linked MR, macroorchidism without the fragile(X). Three other X-linked conditions were identified: in one family, the Coffin-Lowry syndrome, in another, Duchenne muscular dystrophy, and in two families X-linked MR and muscle atrophy. Half (56%) of the obligatory carriers of fra(X)-MR in this study were dull to mildly retarded. The mildly retarded heterozygotes had a significantly higher percentage of fra(X) expressing lymphocytes as compared to the intellectually normal heterozygotes. When the three types of nonspecific X-linked MR for which population frequencies were calculated were considered together, half of the obligatory carriers (46%) were dull or mildly retarded, thus confirming that this condition is a significant cause of mild intellectual handicap in females.

Loss of function mutations in the rsk2 gene cause Coffin-Lowry syndrome (CLS), which is associated with multiple symptoms including severe mental disabilities. Despite the characterization of ribosomal S6 kinase 2 (RSK2) as a protein kinase acting as a downstream effector of the well characterized ERK MAP-kinase signaling pathway, it turns out to be a challenging task to link RSK2 to specific neuronal processes dysregulated in case of mutation. Animal models such as mouse and Drosophila combine advanced genetic manipulation tools with in vivo imaging techniques, high-resolution connectome analysis and a variety of behavioral assays, thereby allowing for an in-depth analysis for gene functions in the nervous system. Although modeling mental disability in animal systems has limitations because of the complexity of phenotypes, the influence of genetic variation and species-specific characteristics at the neural circuit and behavioral level, some common aspects of RSK2 function in the nervous system have emerged, which will be presented. Only with this knowledge our understanding of the pathophysiology of CLS can be improved, which might open the door for development of potential intervention strategies.

The Coffin-Lowry syndrome is an inherited syndrome of mental retardation, characteristic facies and skeletal anomalies. The occurrence of severe manifestations in males, with no instance of male-to-male transmission, suggests an X-linked inheritance. The paper describes seven families from five European Centers.

The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1ob−/− mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1ob−/− mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1ob−/− mice without affecting other organ weight, while a high-protein diet overcame Atf4−/− and Rsk2−/− mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.

Many members of one family have a unique syndrome of mental retardation, small stature, retarded bone age, hypotonia, tapering fingers, a characteristic facies which includes hypertelorism, upturned nares, and prominent frontal region, and possibly arrested hydrocephalus. The evidence suggests an autosomal dominant gene with variable expressivity as the cause of the syndrome.

A family with four severely mentally retarded male members who have odd facial features, broad tapering fingers, and abnormal skeletal development is described. Some female members of the kindred show a milder degree of mental retardation and less marked somatic features. Inheritance appears to be via a dominant trait with the possibility of X-linkage being present. No metabolic abnormality has been demonstrated.