RAPADILINO syndrome

Classification according to ICD-10
Q87.1	Congenital malformation syndromes that are predominantly associated with short stature
ICD-10 online (WHO version 2019)

The rapadilino syndrome is a rare genetic disease that mainly due to congenital malformations in musculoskeletal system , microsomia and cleft lip and cleft palate is characterized. It is based on a mutation in RECQL4 - gene based on the autosomal - recessive inherited. The term "RAPADILINO" is an acronym from the characteristic symptoms .

First description and epidemiology

The RAPADILINO syndrome was first described in 1989 by a Finnish research group led by Helena Kääriänen. Further scientific articles on this topic have been published primarily by researchers from the Universities of Helsinki and Turku , so a prevalence is only given for Finland so far; this is 1: 75000. Further cases in other countries are known.

root cause

The rapadilino syndrome is caused by a mutation in RECQL4 - Gen . This gene codes for the ATP-dependent DNA helicase Q4, an enzyme that splits the two twisted strands ( double helix ) of DNA and thus enables both replication and repair of the DNA. So far, four different mutations are known that lead to the disease. On the one hand, three nonsense mutations have been described (in exons 5, 18 and 19), i.e. mutations that generate a false stop codon and thus lead to the shortening and loss of function of the resulting protein . However, an in-frame deletion occurs much more frequently, with the result that exon 7 is erroneously completely removed from the protein during splicing and therefore 44 of 1208 amino acids are missing. As a result , there is no frame shift .

It is noteworthy that the missing exon 7 in the in frame deletion does not affect the actual helicase domain (the active center ). This means that the structure that performs the actual function of the helicase (cleavage of the DNA double helix) is intact. The malfunction in this case is presumably due to an incorrect folding of the protein, which is caused by the lack of exon 7. The cause of an incorrect convolution could be the shift of the isoelectric point from 8.45 to 8.78; Increased polarity of the entire enzyme can also be considered, since a larger hydrophobic area is omitted in exon 7 with ten proline side chains .

While the cause seems to have been sufficiently clarified at the molecular genetic level, it is currently still unclear how the malfunctioning RecQ helicase leads to the characteristic symptoms. It is believed that the enzyme has an influence on the genetic stability of the cell, which could explain the tendency towards cancer . RecQ helicases have also been found in enterocytes , with a link to malabsorption and diarrhea being seen. Recent research has shown that, in addition to helicase activity, the enzyme's ability to cleave ATP ( ATPase activity) is also missing.

Symptoms

The name “RAPADILINO” was chosen as an acronym from the characteristic symptoms in English, which are shown in the following table.

syllable	English name	German name	German equivalent
RA	RA dial hypo- / aplasia	radial hypoplasia / aplasia	underdeveloped or missing bones in the forearm
PA	PA tellae hypo- / aplasia, cleft or highly arched PA late	Hypoplasia / aplasia of the patella , split or heavily arched palate	Underdeveloped or missing kneecap, malformations in the mouth and palate area (especially cleft lip and palate )
DI	DI arrhoea, DI located joints	Diarrhea , dislocated joints	Diarrhea, displaced or dislocated joints
LI	LI ttle size, LI mb malformation	small size, malformed extremities	Short stature , malformed limbs
NO	slender NO se, NO rmal intelligence	slim nose, normal intelligence	-

In addition, malassimilation has been observed in children, i.e. the inadequate absorption of nutrients from food in connection with frequent diarrhea or vomiting can lead to a form of malnutrition . In addition to malformations in the musculoskeletal system , this can also cause short stature. The occurrence of café-au-lait stains has also been reported.

In RAPADILINO patients, the cancer risk is increased by approx. 40%, with an increased incidence of osteosarcomas and lymphomas in particular .

Diagnosis

The diagnosis of RAPADILINO syndrome is primarily based on the characteristic symptoms, since a DNA analysis aimed at recognizing the mutation is expensive, time-consuming and sometimes imprecise. Due to the inheritance of the disease, genetic counseling can be useful.

In terms of differential diagnosis , the RAPADILINO syndrome must be differentiated from two other diseases, both of which are also based on mutations in the RECQL4 gene and some of the symptoms can be the same: Rothmund-Thomson syndrome and Baller-Gerold syndrome . The former mainly affects the skin, so discoloration of the skin ( poikiloderma ) confirms this diagnosis. The latter mainly leads to malformations of the bony skull . It is worth mentioning that the cancer risk for both diseases seems to be higher than that for RAPADILINO syndrome; this is attributed to the structure of the helicase domain mentioned in the section on causes , which is not retained in the other two syndromes due to a different type of mutation in contrast to RAPADILINO.

therapy

According to the current status, a cure is not possible, so the therapy options are limited to alleviating or eliminating the symptoms. Malformations can be corrected surgically ; if the bones are missing, prostheses can be used. Disorders in the digestive tract can be counteracted with medication; a corresponding direct administration is possibly indicated in the case of severe nutrient deficiency.

literature

• H. Annika Siitonen u. a .: Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. In: Human Molecular Genetics . Volume 12, Issue 21, November 2003, pp. 2837-2844. ISSN  0964-6906 . doi : 10.1093 / hmg / ddg306 . PMID 12952869 . (Text as PDF file , 366 kB)
• RAPADILINO syndrome. In: Orphanet (Rare Disease Database).

Individual evidence

1. ↑ H. Kääriäinen, S. Ryöppy, R. Norio: RAPADILINO syndrome with radial and patellar aplasia / hypoplasia as main manifestations. In: American journal of medical genetics. Volume 33, Number 3, July 1989, pp. 346-351, ISSN  0148-7299 . doi : 10.1002 / ajmg.1320330312 . PMID 2801769 .
2. ↑ ^{a b c d e} H. A. Siitonen, O. Kopra u. a .: Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. In: Human Molecular Genetics . Volume 12, Number 21, November 2003, pp. 2837-2844, ISSN  0964-6906 . doi : 10.1093 / hmg / ddg306 . PMID 12952869 .
3. ↑ ^{a b} Data sheet on RAPADILINO Syndrome in Genetics Home Reference at www.ghr.nlm.nih.gov (accessed on March 28, 2014)
4. ↑ Data sheet ( Memento of the original from April 7, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. on the RAPADILINO syndrome on gentlelabs.com (accessed March 31, 2014) 
5. ↑ DL Croteau, ML Rossi et al. a .: RAPADILINO RECQL4 mutant protein lacks helicase and ATPase activity. In: Biochimica et Biophysica Acta . Volume 1822, Number 11, November 2012, pp. 1727-1734, ISSN  0006-3002 . doi : 10.1016 / j.bbadis.2012.07.014 . PMID 22885111 . PMC 3500628 (free full text).
6. ↑ RAPADILINO SYNDROME.  In: Online Mendelian Inheritance in Man . (English)
7. ↑ HA Siitonen, J. Sotkasiira u. a .: The mutation spectrum in RECQL4 diseases. In: European journal of human genetics. Volume 17, Number 2, February 2009, pp. 151-158, ISSN  1476-5438 . doi : 10.1038 / ejhg 2008.154 . PMID 18716613 . PMC 2986053 (free full text).

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