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Coffin-Lowry syndrome

Síndrome de Coffin-Lowry
José C.S. Guitti, Fabianne F. Peres
J Pediatr (Rio J) 2000;76(4):305-9

Objective: To promote the diffusion of the knowledge on the Coffin-Lowry syndrome and to contribute to the outline of the disease. Methods: Case report.

Results: The clinical signs of a patient with the Coffin-Lowry syndrome are described and discussed.

Conclusions: The Coffin-Lowry syndrome, a X-linked genetic disease, is probably underdiagnosed in Brazil. The typical facies, dental-skeletal anomalies and mental retardation suggest the diagnosis, which can be clinically established by radiographic study of the hands.


Coffin et al. (1), in 1966, and Lowry et al.,(2) in 1971, independently and complementary described mentally retarded patients with characteristic facies. In 1975, Temtamy et al. (3) identified these two syndromes as part of one single entity, which was then named the Coffin-Lowry syndrome (CLS).

CLS is a well-established X-linked syndrome. Biancalana et al.4 confirmed that the RSK2 gene - whose mutation originates the syndrome - is located on the X chromosome. More recently, Schutz et al. (5) identified the exact localization of this gene at Xp22.13-p22.2. Jacquot et al. determined the genomic structure of the RSK2 gene, and showed that diagnosis confirmation can be established by the isolation of the protein that causes the mutation (6).
According to Young,7 58 cases had been described in literature up to 1988. Since then, 35 other patients have been reported.

Although carrier's facies is typical, it is likely that CLS has been underdiagnosed because clinicians may be inadequately trained to carry out dysmorphological examinations. Evidence of such possibility is that there is no reference to any publication in Latin America (Medline, Lilacs) except for two cases reported in Mexico (8).

Case report

A 9-year and 3-month-old white boy from Londrina (Paraná), the only child of a nonconsanguineous couple, born by normal delivery (weight: 3,100 g; height: 49 cm; head and thorax circumferences: 34 cm and 33 cm, respectively). Neonatal period was uneventful. From the 10th month of life on, coarse facial features became apparent, as well as neurological and psychomotor retardation, which accentuated progressively. He has difficulty to walk and needs support, and does not talk. He has been under anticonvulsant treatment for 1 year because of frequent apparently unmotivated falls. He gets tired easily when walking and has had repeated diagnoses of pneumonia. There is no reference of a similar case in the family. The mother denies diseases, ingestion of drugs or medicines, exposure to pollutants or to excessive heat during pregnancy.

Physical examination: weight = 30 kg (25th-50th percentile); height = 117.5 cm (< 2.5th percentile), head circumference = 51 cm (50th percentile); blood pressure = 108 x 65; heart rate = 86 bpm. Protosystolic regurgitation murmur, grade II/VI, in tricuspid and mitral areas; systolic ejection murmur, grade II/VI, in pulmonary area, normal first sound; slightly louder second sound, with fixed unfolding. Clear lungs.

No visceral enlargement. No spinal anomalies. Normal, symmetric limbs. Flat feet. Grotesque facies (Figure 1), with bitemporal narrowing, hypertelorism, downward-slanting palpebral fissures, and thick eyelids. Broad-based nose with a thick septum. Pouting everted lower lip; smooth tongue. Low-set ears. Hypodontia (Figure 2). Thick and loose skin, velvety surface. Small but puffy hands, short fingers, discrete thickening and absence of anomalous hypothenar fold. Unstable, waddling broad-based gait. Reduced osteotendinous reflexes. Right inguinal hernia surgical scar. Normal genitals. Apparently normal hearing. Docile behavior with moments of irritability, utterance of inarticulate sounds to show dissatisfaction.

Figure 1 -
Coffin-Lowry syndrome. Facial aspects.


Figure 2 -
Hypodontia: congenital absence of lateral incisors. Small and narrow central incisors.

Family history: Mother's height in the 10th-25th percentile. Normal aspect, except for a slightly thickened septum, bilateral frontal prominence, and bitemporal narrowing (Figure 3). Father with normal aspect. Maternal grandparents, three uncles, seven aunts and two first-degree cousins reported to have normal appearance. Paternal family reported to be normal (family members were not studied as they live in another state).

Figure 3 -
Patient's mother. Thick nasal septum, bilateral frontal prominence and bitemporal narrowing.


Complementary investigation: Kariotype 46XY (cytogenetic analysis of metaphasic cells). Complete blood count and urinalysis: type I, normal. Chest radiography: no skeletal anomalies; signs of venous stasis in pulmonary circulation; slightly enlarged cardiac area with convex middle aortic arch. Normal spine radiography.

Radiography of lower limbs: short and wide femoral neck. Radiography of the skull and face: absence of frontal sinuses; thickened nasal septum and supraorbital ridge; multiple hypodontia. Radiography of the hands: tapering distal phalanges with tufting (Figure 4). Normal gastroesophageal reflux. Cranial CAT scan: slight cortical atrophy, with mild dilatation of the supratentorial ventricular system.

Electroencephalogram: diffuse irritative encephalic activity. Electrocardiogram: sinus rhythms; low-voltage QRS complexes, and diffuse change in ventricular repolarization. Echodoppler cardiogram: situs solitus; normal segmental analysis; slight enlargement of the four chambers; diffuse, insignificant involvement of the left ventricle; moderate insufficiency of the tricuspid and mitral valves; pressure on pulmonary artery = 69 mmHg; ejection fraction = 0.54; ostium secundum interarterial communication with a diameter of 0.4 cm (Figure 5). Hearing test was not performed.

Figure 4 -
Radiography of the hands. Tapering distal phalanges and tufting.


Figure 5 -
Echodoppler cardiogram. Interatrial communication.



The original descriptions of this syndrome by Coffin et al. (1) and Lowry et al. (2) list the most common clinical signs of CLS: mental retardation, typical and coarse facies, large soft hands with short hyperextensible fingers, and skeletal deformities, mainly of the spine. Other authors subsequently added new characteristics, which are not always present in all cases. The male sex is more severely affected, while in women the manifestations are usually subtle and may be overlooked (3,5).

Short stature becomes progressively apparent in childhood, although it has already been observed as an early manifestation in a 5-month old infant (9). Final adult height is usually well bellow the 2.5 percentile, and may decrease due to the deterioration of spinal lesions (7). Microcephaly is rarely observed in spite of the severe mental retardation. Cerebral ventricular dilation has already been reported (1-3,10), but it is not clear whether it is a consequence of raised intracranial pressure or parenchymal retraction (7). Craniofacial features are consistent and typical, and some outstanding characteristics are: orbital hypertelorism, downward slanting palpebral fissures; broad-based nose with a thick septum; thick lips; and bitemporal narrowing. Hypodontia is frequent, and, in some cases, there is midface hypoplasia in contrast to mandibular prognathism.

Other orodental findings have been described, such as high and narrow palate, malocclusion, and deep midline lingual furrow (11).

Truncal anomalies include pectus excavatum or carinatum and spinal deformities. Inguinal hernia, rectal and uterine prolapse have also been reported (2,3,12), as well as cardiac involvement - mitral insufficiency and cardiomyopathy (1,3,10). There are no records of structural cardiac defects in literature. The interatrial communication in the case presented here may be an accidental circumstance.

The alterations in the extremities are discreet but characteristic. The hands are puffy, with short and hyperextensible fingers, with tapering or fusiform tips. The fingernails may be markedly hyperconvex. Flat feet and shortening of one of the lower limbs may occur and contribute to accentuate the clumsy, waddling gait (3).

Osteocartilaginous involvement may affect the whole skeleton, and is more severe when it affects vertebra and intervertebral disk (1-3,10). Supernumerary ribs and involvement of the pelvis have already been reported.(10) The most remarkable bone anomaly, present in all CLS cases and an indispensable sign for diagnosis, is tapering distal phalanges with tufting (2,13). The most common dermatoglyphic change is the presence of a transverse hypothenar crease (1,3,14), which is evidence enough to suspect this diagnosis (3).

Neurological manifestations also include skull base deformities and important changes in the corpus callosum (15,16). Sensorineural hearing loss and psychosis with a predominant depressive component may also be present (17).

Crow et al (18). have recently questioned the true nature of the convulsive manifestations in CLS carriers. Muscular atony episodes and sudden falls may be a form of cataplexy associated with a neuromuscular dysfunction. This hypothesis has been well supported by the authors with continuous observation of patients (on video), sonography, and muscular biopsy, together with electromyographic and electroencephalographic investigation. The failure of treatments of CLS patients with anticonvulsant drugs supports this hypothesis. Up to this moment, no drug has proven efficient in the control of such manifestations (18).

Repeated pneumonia, probably secondary to problems in swallowing or gastroesophageal reflux, was reported by Bustos Lozano et al. (19) The patient we studied has had four diagnoses of pneumonia, although he does not present the clinical and radiological features compatible with those predisposing factors. Several authors observed that this syndrome's manifestations originate basically from changes in the connective tissue. Coffin et al. (1) detected a greatly reduced number of elastic fibers in the skin and in the subcutaneous tissue, and abnormal arrangement of the chondrocytes. Temtamy et al. (3) found histopathologic signs suggestive of a lysosome storage disorder in one of their patients. Abnormal storage may also occur in cartilage cells (20). These findings, however, have not been confirmed by other authors. Proteodermatan sulfate metabolism was abnormal in cultured fibroblasts (21). If confirmed, all these hypotheses may explain the origin of osteocartilaginous involvement that characterizes this disease, but would not explain the involvement of the nervous system (18).

For infants with suggestive facies and developmental retardation, as well as older children who are not thriving, the following differential diagnosis should be considered: idiopathic hypercalcemia (William's syndrome), embryopathy by hydantoin, trisomy 21, cretinism, mucopolysaccharidosis, Soto's syndrome, fragile X syndrome, and, in adult patients, acromegaly (3,5,10). The syndrome of maternal hyperthermia in pregnancy, which may cause mental retardation and dysmorphisms (11), should also be considered.

Genetic transmission occurred through the women in all families in which several generations where affected, and there is no evidence of male transmission up to the moment (7). Hunter et al. (10) studied 16 pedigrees, and only six had more than one person affected. All the others had only one carrier of this syndrome, which may be the result of de novo mutations. More recently, Jacquot et al. (22) studied a family with four children where two were normal and two presented DNA mutations and CLS clinical features. The mother's lymphocyte DNA did not present signs of mutation.

These findings were consistent with the hypothesis of mutation occurring as a postzygotic event and configuring a germline mosaicism, which would make it impossible to offer conventional genetic counseling for this family and for similar cases. The same authors concluded that, for such reasons, the precise identification of the causing factor in all cases is of paramount importance.

Title of the article: "Coffin-Lowry syndrome"
1. Coffin GS, Siris E, Wegienka LC. Mental retardation with osteocartilagenous anomalies. Am J Dis Child 1966; 112: 205-13.
2. Lowry B, Miller JR, Fraser FC. A new dominant gene mental retardation syndrome: association with small stature, tapering fingers, characteristic facies, and possible hydrocephalus. Am J Dis Child 1971; 121: 496-500.
3. Temtamy AS, Miller JD, Hussels-Maumenee I. The Coffin-Lowry syndrome: an inherited faciodigital mental retardation syndrome. J Pediat 1975; 86: 724-31.
4. Biancalana V, Trivier E, Weber C, Weissenbach J, Rowe PS, O’Riordan JL et al. Construction of a high-resolution linkage map for Xp22.1-p22.2 and refinement of the genetic localization of the Coffin-Lowry syndrome gene. Genomics 1994; 22: 617-25.
5. Schutz CK, Ives EJ, Chalifoux M, MacLaren L, Farrell S, Robinson PD et al. Regional localization of an X-linked mental retardation gene to Xp21.1-Xp22.13 (MRX38). Am J Med Genet 1996; 64: 89-96.
6. Jacquot S, Merienne K, De Cesare D, Pannetier S, Mandel JL, Sassone-Corsi P et al. Mutation analysis of the RSK2 gene in Coffin-Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations. Am J Human Genet 1998; 63: 1631-40.
7. Young ID. The Coffin-Lowry syndrome. J Med Genet 1988; 25: 344-48.
8. Barajas LO, Rivera H, Fragoso R, Nazara Z, Cantu JM. Síndrome Coffin-Lowry: descripción de dos casos. Bol Med Hosp Inf Mex 1986; 43: 378-81.
9. Wilson WG, Kelly TE. Early recognition of the Coffin-Lowry syndrome. Am J Med Genet 1981; 8: 215-20.
10. Hunter AGW, Partington MV, Evans JÁ. The Coffin-Lowry syndrome. Experience from four centres. Clin Genet 1982; 21: 321-35.
11. Salinas CF. Orodental findings and genetic disorders. Birth Defects 1982; 18: 79-120.
12. Kousseff BG. Coffin-Lowry syndrome in an Afro-American family. Am J Med Genet 1982; 11: 373-5.
13. Smith DW. Síndromes de malformações congênitas. 2a ed. São Paulo: Ed. Manole; 1997. p.273-4.
14. Procopis PG, Turner B. Mental retardation, abnormal fingers, and skeletal anomalies. Coffin’s syndrome. Am J Dis Child 1972; 124: 258.
15. Tokumaru AM, Barkovitch AJ, Ciricillo SF, Edwards MS. Skull base and calvarial deformities: association with intracranial changes in craniofacial syndromes. Am J Neuroradiol 1996; 17: 619-30.
16.Soekarman D, Fryns JP. Corpus callosum agenesis in Coffin-Lowry syndrome. Genetic Counseling 1994; 5: 77-80.
17. Sivagamasundari U, Fernando H, Jardine P, Rao JM, Lunt P, Jayewardene SL. The association between Coffin-Lowry syndrome and psychosis: a family study. J Intellec Disab Res 1994; 38: 469-73.
18. Crow YJ, Zuberi SM, McWilliam R, Tomie JL, Hollman A, Pohl K, et al. “Cataplexy” and muscle ultrasound abnormalities in Coffin-Lowry syndrome. J Med Genet 1998; 35: 94-8.
19. Bustos Lozano G, Barrionuevo Porras JL, Sanchez de Pozo J, Lledo G, Gallego M. Coffin-Lowry syndrome with repeated pneumonia. An Esp Pediat 1988; 28: 451-3.
20. Gorlin RJ, Brown D, Sauk J. Coffin-Lowry syndrome – a storage disorder? Birth Defects 1978; 14: 175.
21. Beck M, Glössl J, Rüter R, Kresse H. Abnormal proteodermatan sulfate in three patients with Coffin-Lowry syndrome. Pediat Res 1983; 17: 926-29.
22. Jacquot S, Merienne K, Pannetier S, Blumenfeld S, Schinzel A, Hanauer A. Germline mosaicism in Coffin-Lowry syndrome. Eur J Human Genet 1998; 6: 578-82.
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