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The Coffin-Lowry syndrome has become well established since the first report of affected patients by Coffin et al. [1966: Am J Dis Child 112:205-213]. Since that time over a hundred cases have been reported and the responsible gene has been identified. However, there remains a paucity of long-term follow-up information on older patients with which to counsel affected families about prognosis. There is also much to be learned about genotype-phenotype correlations. In 1982 we reported 12 patients (including carrier mothers) from eight families, one of whom had died about the time the paper was written. Recently, we have been able to obtain follow-up information on six of the affected patients and one of the carrier mothers. A number of important complications have occurred, including premature death, loss of ambulation, and quadriplegia. This paper updates the medical histories of our patients and summarizes the clinically important complications that have been reported in patients with Coffin-Lowry syndrome. There are few data on patients over the age of 30, and much more longer term follow-up is required.

We recently evaluated a mentally retarded 48 year old man found to have a cytogenetic deletion of chromosome 10 [46,XY,del(10) (q25. 1q25.3)]. Of interest, he shares many clinical findings with those described in Coffin-Lowry syndrome (CLS). These include severe mental retardation, short stature and a coarse facial appearance with widely spaced eyes, and patulous lips. He also had an extra transverse hypothenar crease, a finding that is seen in CLS. Furthermore, he has characteristic radiographic hand findings described in 95% of patients with CLS. The CLS gene, located at Xp22. 2, has recently been identified, and mutations in the Rsk-2 gene have been identified in several CLS patients. Rsk2 is part of a gene family implicated in cell cycle regulation through the mitogen-activated protein (MAP) kinase cascade. None of the currently recognized components of this pathway maps to the region deleted in our patient, nor are we able to identify any likely candidate genes in the deleted region, although several G protein coupled receptors have been cloned from the region. This patient's findings have some overlap with those seen in CLS, suggesting that a gene involved in MAP kinase signaling may be present in the deleted region of chromosome 10q25.1-25.3. Patients with a phenotype consistent with CLS, but lacking a family history suggestive of an X-linked disorder, should be evaluated with chromosome analysis paying particular attention to the region 10q25.

Coffin-Lowry syndrome (CLS) is a rare but well-documented X-linked disorder characterized by small size, developmental delay/mental retardation, and characteristic facial and skeletal findings in affected males. The phenotype in affected females is far more variable and can include developmental differences, obesity, and characteristic facial and skeletal differences. Cardiac anomalies are reported in less than 20% of affected males, with cardiomyopathy being one of the rare but reported complications of this disorder. However, cardiomyopathy is not well characterized in CLS. Here, we report on a 14-year-old boy with physical and developmental findings consistent with CLS who presented with a relatively sudden onset of signs of congestive heart failure due to a restrictive cardiomyopathy; an endomyocardial biopsy demonstrated non-specific hypertrophic myocyte alterations consistent with cardiomyopathy. This is the first description of the histology and electron microscopy of cardiomyopathy in CLS.

Coffin-Lowry syndrome (CLS; MIM 303600) is an uncommon X-linked disorder causing mental retardation and skeletal abnormalities. Most recently it was mapped to a 5.6-centimorgan (cM) region of Xp22, flanked distally by AFM291 wf5 and proximally by DXS1052 [Biancalana et al., 1994: Genomics 22:617–625]. We present information which supports this localization and further narrows the region to approximately 3.4 cM. A recombination in a carrier from a British family means that DXS365 is the closest proximal flanking marker identified to date for the region thought to contain the CLS gene. This information reduces the region of interest by approximately 2.2 cM, a significant decrease in terms of the scale of effort which will be required to isolate and analyze candidate genes. © 1995 Wiley-Liss, Inc.

We report on 7 patients (6 M, 1 F) with Coffin-Lowry syndrome who have a sensorineural hearing deficit in addition to developmental delay and characteristic facial changes. One of the patients also had a history of premature exfoliation of primary teeth. These are previously unappreciated clinical signs that may aid in the early diagnosis of Coffin-Lowry syndrome. Early diagnosis and recognition of a hearing deficit in the patient can lead to the use of hearing aids to help the patient achieve his or her full potential. These "new" clinical manifestations expand the phenotype of Coffin-Lowry syndrome and constitute an additional indication of pleiotropy.

Two unrelated infants with delayed development and suspected abnormalities of the upper limbs were found to have the Coffin-Lowry syndrome. Both had marked fullness of the forearms in the presence of normal skeletal structures which resulted from increased subcutaneous fat. Although initially misleading, the forearm changes may serve as an early diagnostic clue in this disorder.

We report a 2-year-old male infant with the Coffin-Lowry syndrome, and describe the change in his clinical and radiographic manifestations during the first 2 years of life. Review of published cases of the Coffin-Lowry syndrome indicates that these manifestations are progressive, and that all of the associated characteristics may not be apparent in early childhood. The importance of continued evaluations of these patients and examination of relatives for mild manifestations is emphasized.

The authors report the Coffin-Lowry syndrome in two sibs and suggest autosomal recessive inheritance of the condition in this family.

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.

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.

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.