Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome.

PURPOSE: Loss-of-function mutations in FGFR1 have been identified in approximately 10% of the Kallmann syndrome (KS) patients. Previous reports have focused mainly on olfactory, reproductive, and some other features such as cleft lip/palate and dental agenesis. Given the ubiquitous expression of FGFR1 during development, other abnormal phenotypes might, however, have been overlooked in these patients. Here, we demonstrate skeletal phenotypic characterization of patients presented with KS and FGFR1 mutations. MATERIAL AND METHODS: Using the Sanger DNA sequencing technique a cohort of 29 KS patients was screened. RESULTS: Here, we report on 5 KS patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Three patients presented with skeletal abnormalities, i.e. spine (hemivertebra and butterfly vertebra) and limb (oligodactyly of the feet, fusion of the 4th and 5th metacarpal bones) malformations in two patients and one patient, respectively. The hand phenotype found in the patient cannot be thought of as a counter-type of the hand phenotype resulting from FGFR1 gain-of-function mutations. The skeletal anomalies identified in the 3 KS patients are close to those observed in Fgfr1 conditional knockout mice. CONCLUSIONS: This study demonstrates that FGFR1 loss-of-function mutations can be associated with skeletal abnormalities also in humans. Further investigations in KS patients who carry FGFR1 mutations are needed to evaluate the prevalence of skeletal defects in this genetic form of KS. Conversely, the presence of bone malformations in a KS patient should direct the geneticist towards a search for mutations in FGFR1.

Reciprocal chromosome translocations involving short arm of chromosome 9 as a risk factor of unfavorable pregnancy outcomes after meiotic malsegregation 2:2.

PURPOSE: Genetic counseling of carriers with individual chromosome translocation requires information on how balanced reciprocal chromosome translocations (RCT) will segregate, what possible form of unbalanced embryo/fetus/child can occur, and the survival rates that have been observed in the particular families. We collected new empirical data and evaluated pedigrees of RCT carriers involving 9p in order to improve risk figures. MATERIAL AND METHODS: Empirical data on 241 pregnancies of 70 carriers were collected from 32 pedigrees of carriers of RCT at risk for a single 9p segment imbalance (RCT9p) from the literature and unpublished data. The probability rates of particular types of pathology have been calculated according to the method of Stengel-Rutkowski and Stene. Cytogenetic interpretation was based on GTG, RBG and FISH techniques. RESULTS: The probability rate for unbalanced offspring at birth for the whole group of pedigrees was calculated as 17.8+/-3% (33/185) (high risk). Considering the size of the imbalanced segment of 9p, the probability rates for RCT carriers with a breakpoint position at 9p22 at 9p13 and at 9p11.2 were estimated separately, and were found as 21.2+/-4.4% (18/85), 25+/-8.8% (6/24) and 11.8+/-3.7% (9/76), respectively. For unbalanced fetuses at 2nd prenatal diagnosis, we found the risk value as 57.9+/-11.3 % (11/19). The risk value for unkaryotyped stillbirths/early deaths of newborns and miscarriages were 5.4+/-1.7% (10/185) (medium risk) and 13+/-2.8% (rate 24/185) (high risk) respectively. CONCLUSIONS: Our results showed that the recurrence probability rates are different for particular categories of unfavorable pregnancy outcomes. How much they are dependent on the size of 9p chromosome segments taking part in the imbalance needs further studies based on a larger number of observations.

Prenatal evaluation of a fetus with trisomy 18 and additional balanced de novo Rob(13;14).

The main aim of this work is to present unusual case with full trisomy 18 and additional robertsonian translocation- Rob (13;14) detected through abnormalities found in prenatal ultrasound examination. A 26 years-old pregnant women with no family history of any reproductive failure underwent level II ultrasound screening in 19 weeks of gestation. Polyhydramnios, intrauterine growth retardation, hydrocephalus, enlarged lateral ventricles, club foot and cardiac defect were found. Amniocentesis was indicated considering the high likelihood of a chromosomal aberration. Abnormal karyotype was detected 46, XY, der(13;14)(q10;q10), +18. Karyotypes of parents were normal, what confirmed de novo origin of this aberration. Pregnancy was terminated. In postnatal examination fetus demonstrated intrauterine groth retardation and a lot of dysmorphic features characteristic for trisomy 18: microcephaly, prominent occiput, very low set and posteriorly rotated ears, hypertelorism, small mouth, small recessed mandible, a high narrow palate, broad nasal bridge, low-set ears, preauricilar skin appendage, clenched fingers clinodactyly of Vth fingers and club foot. In conclusion it is worth to say that our described fetus demonstrated rather typical for trisomy 18 ultrasonographic features. Balanced Rob (13;14) gives no phenotypic expression. Possible interchromosomal effect in complex chromosomal aberration formation such as Rob (13;14) with trisomy 18 was discussed.

Translocation form of Wolf-Hirschhorn syndrome --assessment of recurrence rate probability.

PURPOSE: The families experienced by occurrence of child with Wolf-Hirschhorn syndrome (WHS: OMIM # 194190) and by other unfavourable pregnancy outcomes (miscarriages or stillbirths/early deaths and partial trisomy 4p imbalance leading to intellectual disability in live born progeny) are asking for genetic counseling. In order to obtain the recurrence probability rates for the particular forms of unfavourable pregnancy we collected the empirical data and evaluated pedigrees of reciprocal chromosome translocations (RCT) carriers involving 4p. Results were applied to family of carrier of t(4;11)(p16.1;q23.3) ascertained by four miscarriages, in which latter the girl with WHS was born. MATERIAL AND METHODS: Total empirical data about 170 pregnancies of 46 carriers were collected from 25 pedigrees RCT at risk for single segment imbalance. Classification was based mostly on cytogenetic methods. The probability rates of particular type of pathology related to total number of pregnancies after ascertainment correction have been calculated according to the method of Stengel-Rutkowski and Stene. RESULTS: The risk figures for unbalanced offspring after 2:2 disjunction and adjacent-1 segregation for whole group of pedigrees were calculated as 15.2 +/- 3.5% (16/105), for unbalanced fetuses at second trimester of prenatal diagnosis as 50 +/- 13.4% (7/14), for miscarriages about 19 +/- 3.8% (20/105) and for stillbirths/early death as 15.2 +/- 3.5% (16/105). The higher probability rate for RCT carriers at risk for distal 4p--shorter segment imbalance (28.6 +/- 12%, 4/14) in comparison to the rate for proximal (medium) one as 15.4 +/- 4.5% (10/65) and to more proximal (longer) one as 7.7 +/- 5.2% (2/26) were found. CONCLUSIONS: Our results confirm that the recurrence probability rates are different for particular categories of unfavourable pregnancy outcomes and dependent on size and genetic content of unbalanced 4p segments.

[Prenatal and neonatal diagnosis of osteogenesis imperfecta in obstetrical practice]. / Diagnostyka przed i pourodzeniowa wrodzonej lamliwosci kosci (Osteogenesis imperfecta) w praktyce polozniczej.

Osteogenesis imperfecta (OI types I, II, III, IV) is a heterogeneous group of genetically disorders of connective tissue. Quantitative or qualitative abnormalities of type I collagen form pathogenetical basis of the disease. They are caused by mutations in genes encoding collagen proteins or enzymes involved in collagen biosynthesis. The clinical features of each type usually correspond to the type of mutation. Typical manifestations are fragile bones with multiple bone fractures and bone deformities. Currently applied diagnosis in utero of OI II and sometimes OI III may be performed. Diagnosis of other OI phenotypes cannot be made until after birth. We present three cases of OI II (four children) diagnosed, in utero, by ultrasound examination. The analysis in work include: 1. the prenatal sonographic features of OI type II 2. the biochemical properties of collagen in the above cases 3. genetic counselling of the families affected by OI.

Defects of type I procollagen metabolism correlated with decrease of prolidase activity in a case of lethal osteogenesis imperfecta.

We have studied the structure and metabolism of type I procollagen in a case of perinatal lethal osteogenesis imperfecta (OI) type II. Cultured skin fibroblasts from the proband synthesized both normal and abnormal forms of type I procollagen. Some abnormal, overmodified molecules were secreted by OI cells, although less efficiently than normal molecules from control cells. The OI fibroblasts accumulated large amounts of abnormal proalpha1(I) and proalpha2(I) chains intracellularly. The extracellular collagenolytic activity was decreased compared to control cells. Furthermore, OI cells produced less type I procollagen and demonstrated lower capacity to synthesize DNA than control cells. We have found that in contrast to prolinase activity, the activity of prolidase (an enzyme essential for collagen synthesis and cell growth) is also significantly reduced in OI cells. No differences were found in the amount of the enzyme protein recovered from both the OI and control cells. However, we found that expressions of beta1 integrin and insulin-like growth factor-I receptor (receptors known to play an important role in up regulation of prolidase activity) were decreased in OI cells compared to control cells. The decrease in prolidase activity may provide an important mechanism of altered cell growth and collagen metabolism involved in producing the perinatal lethal form of the OI phenotype.

Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY gonadal dysgenesis cases without SRY mutations.

Mutations in the Y-located testis-determining gene SRY are one cause for XY sex reversal. We have previously identified four SRY mutations in a total of 45 sex-reversed females with XY gonadal dysgenesis (XY GD). In a new sample of 16 XY GD cases, three previously undescribed SRY mutations were identified. Two are point mutations that lead to amino acid substitutions in the HMG domain of SRY, M64R, and F67V. The third SRY mutation is a single base insertion 5' to the HMG box within codon 43, converting this lysine codon to a stop codon (K43X). A total of 33 SRY mutations have so far been described that account for only 10-15% of XY GD females. A further 10-15% of these cases result from deletion of SRY due to aberrant X/Y interchange. The etiology of the remaining 70-80% of XY GD cases is still enigmatic. Possible explanations for these XY sex-reversal cases are discussed.

[Ultrasound diagnosis of four fetuses with Fraser syndrome during pregnancy]. / Ocena ultrasonograficzna czterech plodów z zespolem Frasera w okresie ciazy.

The authors present results of sonography analysis of four fetuses with Fraser syndrome. First woman had prenatal diagnosis by ultrasounds and ascites of fetus with polyhydramnion were diagnosed in two of her successive pregnancies. The second pregnant woman was observed by ultrasound and lack of kidney was detected. The third pregnant one was diagnosed at first trimester of pregnancy and results of sonography examination were at norm. After delivery, Fraser syndrome in all of these children was diagnosed. Findings on sonography included: ascites of fetus, polyhydramnion, hydrocephalus and nonvisualization of kidney. Sonography is more efficient in the diagnosis of Fraser syndrome in a fetus whose parents had had a previous affected child because of diverse anomalies were observed.

[Familial complex chromosome translocation of t(1;4;10)(q21.3;q27;q26.1) verified by FISH]. / Rodzinne wystepowanie zlozonej translokacji chromosomowej t (1;4;10) (q21.3;q27;q26.1) zweryfikowanej metoda FISH.

The inheritance complex chromosome translocation is a rare. A familial complex chromosome rearrangement t(1;4;10)(q21.3;q27;q26.1) involving three chromosomes ascertained due to four spontaneous abortions in phenotypically normal childless woman there is presented. Cytogenetic analysis according to classic banding techniques were verified by fluorescent in situ hybridization (FISH) technique.

[The case of intrauterine pregnancy coexisting with extrauterine pregnancy which was surgically removed]. / Przypadek ciazy wewnatrzmacicznej z jednoczesnym wspólistnieniem ciazy pozamacicznej usunietej operacyjnie.

The case of simultaneous intrauterine and ruptured ectopic pregnancy was presented. The diagnosis of coexisting intrauterine and ectopic pregnancies is difficult. The patient was admitted to the clinic because of abdominal pain and vaginal bleeding in the 10th week of pregnancy has been treated by laparotomy. The intrauterine pregnancy was continued successfully to term. The importance of careful sonographic examination of adnexal region was stressed in all symptomatic patients with first trimester pregnancy.

[Pedigree analysis of childless families of reciprocal chromosome translocation carriers]. / Analiza rodowodowa bezdzietnych rodzin obciazonych nosicielstwem translokacji chromosomowych wzajemnych.

OBJECTIVES: Pedigree analysis of childless families of unique reciprocal chromosome translocation (RCT) carriers may be useful for clinical prognosis and genetic counselling. MATERIAL AND METHODS: The group 13 childless families of RCT carriers were detected. Cytogenetic analysis of RCT was performed on blood samples using GTG and RBG banding technique. RESULTS: Thirteen pedigrees were constructed on basis of 64 cytogenetic results and anamnestic data of 62 spontaneous abortions and 7 stillbirths. Familial RCT were found in ten families. In addition fourteen relatives of the RCT carriers have had healthy children. Further observations showed other three healthy children among progeny of eight families. Low risk for unbalanced progeny at birth were estimate in most families. CONCLUSION: Childless families of RCT carriers have possibility to have healthy offsprings. Spontaneous abortions are result of RCT carrierstrip.

[Spontaneous menstruation in patients with Turner syndrome in our observations]. / Samoistne miesiaczkowanie u pacjentek z zespolem Turnera--wlasne obserwacje.

OBJECTIVES: Patients with Turner syndrome (TS) may present a wide spectrum of gonadal function including spontaneous menstruation and fertility. DESIGN: The aim of our study was to present the patients with Turner syndrome (TS) with spontaneous menstruations considering specific karyotype and X-inactivation processes. MATERIALS AND METHODS: 5 women from group of 55 patients in age from 15 to 38 years with diagnosis of TS and gonadal function were found. Clinical analysis included the evaluation of spontaneous pubertal development and hormones levels. Cytogenetic analysis was performed on peripheral blood samples using GTG banding technique. X inactivation studies were done by dynamic RBG technique. RESULTS: In two patients with mosaic karyotype and predominant 46,XX line two pregnancies were observed. They had regular menses and normal sexual development. In one patient (karyotype: 45,X[2]/46,XX[98]) spontaneous abortions and premature birth were present. Second patient was (46,XX[245]/46,X,r(X)(p22q26)[5]) in pregnancy in this time. Another three patients menstruated irregularly. The menarche appeared later. The karyotypes were: 46,X,del(X)(p11.3) in two patients and 45,X[64]46,X,r(X) (p22q26)[18]/46,XX[4] in one. CONCLUSIONS: We conclude that spontaneous menstruations and possibility of pregnancy depend on specific karyotype in patients with TS.

Changing trends in the diagnosis of endometriosis: a comparative study of women with pelvic endometriosis presenting with chronic pelvic pain or infertility.

OBJECTIVE: To compare demographic, epidemiologic, and medical data and to evaluate diagnostic trends in women with endometriosis and chronic pelvic pain symptoms or endometriosis and infertility. DESIGN: Retrospective analysis. SETTING: Institute for the Study and Treatment of Endometriosis. PATIENT(S): Six hundred ninety-three consecutive patients with endometriosis and chronic pelvic pain (n = 357) or endometriosis and infertility (n = 336). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Demographic and epidemiologic parameters, diagnostic trends. RESULT(S): Women with pelvic symptoms were younger, had less formal education, more frequent family history, and higher frequency and intensity of pelvic complaints. Mean ages at first symptom and diagnosis were lower in the pain group, but stage of endometriosis at first diagnosis was more advanced. The mean "diagnostic delay" was longer in the pelvic pain than in the infertile group (6.35 versus 3.13 years), but it decreased during three consecutive 5-year intervals in both groups, and there was also a gradual decrease in the frequency of advanced endometriosis at the time of first diagnosis. CONCLUSION(S): Demographic and epidemiologic parameters in women with endometriosis differ, depending whether chronic pelvic pain or infertility are the presenting symptoms. In the pain group, diagnostic delay is longer and endometriosis at diagnostic laparoscopy more advanced, indicating progressiveness of the disease. During the last 15 years, diagnostic delay steadily decreased and the frequency of advanced endometriosis at first diagnosis declined.

[Clinical examinations, chromosomal and molecular DNA in patients with Swyer syndrome]. / Badanie kliniczne, chromosomowe i molekularne DNA u pacjentek z zespolem swyera.

Two girls with Swyer syndrome (SS) were described. Diagnosis was established according to clinical data and ultrasound, laparoscope, histopathological, hormonal and cytogenetical examinations. One presents diagnostic possibilities followed advanced methods in genetics. The GTG and RBG high resolution bounding technique and replication analysis of short arms (Xp and Yp) were employed. Normal structure of end segments of X and Y chromosomes was mentioned. Molecular DNA analysis by polymerase chain reaction (PCR) did not find any mutation in SRY gene. Normal structure of this gene does not exclude possibility of SS existence. Our data implicates on the other mechanism of these disturbances.

Different risks in two familial translocations t(9;12) with similar breakpoints.

The risk of offspring with unbalanced karyotypes born to carriers of reciprocal chromosomal translocation (RCT) is important to evaluate for further family planning and prenatal diagnosis. The authors describe two families with carriers of similar RCT concerning breakpoint positions and discuss the different individual risks for abnormal progeny. These translocations were studied by GTG, RBG and CBG banding. They have the same breakpoint on 9p, i.e. 9p22, and a different one on 12p, i.e. terminal (pter----p13) and intermediate (p11.2), respectively. The risk value of 27% for family 1 was obtained directly from the large enough pedigree (high risk) a risk value of about 5% was estimated for family 2, according to the guidelines of Stene and Stengel-Rutkowski (1988). The data show that similar translocations with only slight differences in the breakpoints position have different risks for unbalanced progeny. Results of these empiric findings may be used directly in genetic counselling of a family with RCT leading to a single imbalance of the same segment.